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Zanin, Sofia (2014) Effects of different CK2 inhbition strategies in tumor cells. [Tesi di dottorato]

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Abstract (inglese)

Protein kinase CK2, constituted by two catalytic (a and/or a’) and two regulatory (b) subunits, is a highly conserved kinase which phosphorylates a huge number of substrates and is involved in different cellular pathways and functions. It has a major anti-apoptotic role, it enhances the apoptosis resistance (MDR) phenotype, and it is abnormally expressed in a wide variety of cancers, where it operates as a “cancer driver” by creating a cellular environment favorable to the development, growth and propagation of malignancy. Since CK2 expression is not linked to a specific type of cancer, its targeting could be a successful strategy, because of its very general applicability and widespread effects. Importantly, tumor cells are more sensitive to CK2 inhibition than normal ones, probably because they rely more on CK2 for their survival, accordingly to the concept of cancer addition to CK2 (Ruzzene and Pinna, 2010). Therefore, CK2 represents a suitable target for developing anticancer drugs.
Different compounds have been developed so far as CK2 inhibitors, useful not only for investigating CK2 physiological functions, but also as possible therapeutic tools. The majority of them act targeting the ATP-binding site of CK2; some compounds have shown high potency and specificity toward the kinase, and have disclosed a proapoptotic effect in cancer cells more evident than in normal ones.
The research presented in this thesis provides examples of different strategies to target protein kinase CK2, in order to selectively reduce its activity in tumor cells and to produce cellular effects which can counteract the malignant transformation. In particular, we used: 1) CX-4945 and CX-5011, ATP-competitive CK2 inhibitors (Pierre et al. 2011); 2) K137-E4, a bi-functional inhibitor designed to compete with both the ATP and the peptide binding sites of CK2; 3) a compound called CRIBI-300, derived from CIGB-300, designed to prevent the phosphorylation of specific CK2 substrates (Perea et al., 2004). The three studies are summarized below. A fourth study is also described, which exploited a compound, TBID, developed from a CK2 inhibitor but modified to become selective toward another protein kinase, HIPK2.

Effects of the ATP-competitive CK2 inhibitors CX-4945 and CX-5011 in apoptosis-resistant cells

CX-4945 and CX-5011 inhibitors (developed by Cylene Pharmaceuticals) act competing with ATP for the binding to the catalytic pocket of the CK2. These compounds are very potent and selective in inhibiting CK2 (Pierre at al., 2011; Battistutta et al., 2012): CX-4945, in particular, has shown good pharmacological features and has advanced in clinical trials with promising outcomes. However, the CX compounds had never been used in apoptosis-resistant cells. In this work we demonstrate that CX-4945 and CX-5011 are efficient in reducing endogenous CK2 activity and in inducing apoptosis in several pairs of apoptosis-sensitive and resistant tumor cell lines. Furthermore, we also observed that resistant cells which express the drug-extruding pump P-gp are sensitized by CX-4945 towards conventional antitumor drugs. In fact, we found that doxorubicin uptake in resistant cells is increased, and that combined treatment with CX-4945 and vinblastine produces synergistic effects on cell death. In summary, our data suggest that CX inhibitors can be considered as a valid therapeutic strategy also in case of pharmacological resistance.
Effects of CK2 bi-functional inhibitors in tumor cells
A very new strategy to target CK2 is based on compounds denoted as bi-functional or bi-substrate inhibitors, designed to hit both the ATP and the substrate sites of the kinase at the same time, in order to improve selectivity toward CK2. Among these compounds, K137-E4 has been recently developed in our laboratory and characterized by in vitro studies; it was found to strongly inhibit recombinant CK2 (IC50=0.025 uM) and to be very selective. In the study presented in this thesis, we had the aim of investigating the employment of this compound in cells. We first demonstrated that it is also able to inhibit the activity of native CK2 towards cellular substrates. However, this was performed by means of in vitro phosphorylation assay, while, when we used K137-E4 for cell treatment we did not observed any effect on CK2 activity and cell viability. We therefore supposed that the compound, quite hydrophilic, is not cell permeable. Studies are under investigation to modify the molecule structure in order to improve its cell permeability, without significantly decreasing its inhibitory capacity. At present, we found that the K137-E4 molecule, in virtue of its impossibility to cross plasma membrane, can be useful to study CK2 ecto-kinase, that portion of this enzyme that resides at the external surface of cells (Kubler et al., 1989). We demonstrated that it is able to inhibit CK2 ecto-kinase, but this has not effect on cell viability of tumor and non-tumor cells. This finding, in conjunction with the observation that CK2 ecto-kinase activity seems to be similar in tumor and not-tumor cells, suggests that CK2 ecto-kinase is not implied in cell survival and tumor-related events.
In vitro and in cell effects of peptides targeting CK2 substrates
A recently introduced approach to target CK2 is based on the development of a cyclic peptide called CIGB-300, which interferes with the phosphorylation site of specific CK2 substrates, rather than inhibiting the enzyme per se (Perea et al., 2004). CIGB-300 is already employed in clinical trials (Perea et al., 2011), however, its mechanism of action is only partially understood. We therefore exploited a new synthetized peptide, denoted as CRIBI-300, with the same functional domain of the parental CIGB-300, and we performed in vitro and in cell studies, comparing it with CIGB-300 and several other derivatives. We found that CK2 activity in vitro is affected by CRIBI-300 peptide, but with different effects accordingly to the type of substrate used: inhibition is observed only towards substrates which are strictly dependent on the presence of CK2 b for their phosphorylation by CK2, while the activity towards substrates which are preferentially phosphorylated by the CK2 monomeric a is rather stimulated by CRIBI-300. This suggests that CRIBI-300 could interfere with the CK2 holoenzyme structure, producing an unstable and/or unfunctional tetrameric conformation which prevents the phosphorylation of b-dependent substrates.
When we performed cell treatment experiments, we also found that CRIBI-300 induces a strong reduction of endocellular CK2 activity, but this is accompanied by an early and rapid loss of CK2 protein amount. In parallel, cell death was also induced by CRIBI-300, but it was not due to apoptosis. Moreover, we observed a loss in the amount of also other proteins beside CK2; alteration in the activity of proteolytic systems occurs as well, with the activation of lysosomal proteases and the blockage of proteasome machinery. All the effects appear more evident in tumor than in non-tumor cells.
We then analyzed the effects of CRIBI-300 derived peptides, with single aminoacid substitutions or large sequence differences. Interestingly, we found that the Tat sequence (the portion of CRIBI-300 introduced to render it cell permeable (Holm et al., 2006)) is essential for its activity towards CK2 in cells, but not sufficient per se, being specific aminoacids in the remaining part of CRIBI-300, crucial for producing effects.
Of the many effects evoked by CRIBI-300, we wondered if and which ones are mediated by its action on CK2. We found that the reduction of CK2 expression (obtained by RNA-interference cellular experiments) also attenuates some of the CRIBI-300 effects, although not all. Moreover, those CRIBI-300 sequence alterations which prevent in vitro effects on CK2 are also able to reduce cellular effects. We therefore concluded that CK2 is indeed an early and important target of CRIBI-300. However, additional mechanisms of action of this compound should exist to explain all the observed effects, and this suggests that extreme caution is required for its employment at a clinical level.

Effects of TBID inhibitor on cellular HIPK2 activity
A collateral study presented in this thesis concerns a compound, TBID, derived from a CK2 inhibitor (TBI) but modified in structure to become selective for a different kinase, HIPK2 (homeodomain-interacting protein kinase 2), a Ser/Thr kinase controlling cell proliferation and survival (D’Orazi et al., 2012), whose investigation has been hampered by the lack of specific inhibitors able to dissect its cellular functions. TBID is an ATP-competitive inhibitor very potent towards HIPK2 in vitro (IC50= 0.33 μM) and very selective. Here we show that it is also cell permeable, being able to inhibit endocellular HIPK2 activity, and to reduce the phosphorylation state of a HIPK2 target, Ser46 of p53 protein. Since TBID is not cytotoxic under the conditions used to check its effects on cellular HIPK2 activity, we propose TBID as the only tool presently available to down regulate cellular HIPK2.

Altogether, the results presented in this thesis demonstrate that kinase inhibition is an extremely versatile tool to be used in cells, exploitable either to investigate on the role of a specific kinase or to block an unwanted hyperactivity. In particular, in the case of CK2 inhibitors, we analyzed different strategies. Although for the moment the more effective and convincing one is still that represented by the classical ATP-site directed compounds, other approaches are also presented, which need further investigation but could be promising in term of improved specificity or more targeted effects.




Abstract (italiano)

La proteinchinasi CK2, costituita da due subunità catalitiche (a e/o a ') e due subunità regolatorie (b), è un enzima altamente conservato, che fosforila un gran numero di substrati ed è coinvolto in diverse vie di segnale e funzioni cellulari. CK2 svolge un importante ruolo anti-apoptotico, è coinvolta nel fenomeno della farmacoresistenza all’apoptosi, ed è altamente espressa in un'ampia varietà di tumori, dove opera come un "promotore cancerogeno" creando un ambiente cellulare favorevole alla sviluppo, alla crescita, e alla propagazione della malignità. Poiché la sua sovraespressione non è direttamente connessa ad uno specifico tipo di tumore, colpire CK2 può diventare un’ interessante strategia di successo data la sua generale applicabilità e suoi diffusi effetti. È importante sottolineare che le cellule tumorali sono più sensibili all'inibizione di CK2 rispetto a quelle normali, probabilmente perché sono più dipendenti da CK2 per la loro sopravvivenza, e questo va in accordo con il recente concetto di “cancer addiction” a CK2 (Ruzzene e Pinna, 2010). Pertanto, CK2 rappresenta un obiettivo adatto per lo sviluppo di farmaci antitumorali.
Finora sono stati sviluppati diversi inibitori di CK2, utili non solo per indagare il suo ruolo fisiologico, ma sfruttati anche come possibili strumenti terapeutici. La maggior parte di questi composti agisce bloccando il sito di legame per l’ATP dell’enzima; alcuni di questi hanno dimostrato elevato potere inibitorio e specificità verso la chinasi, e si sono rivelati più efficaci nell’indurre apoptosi in cellule tumorali rispetto a quelle normali.
La ricerca presentata in questa tesi fornisce esempi di diverse strategie di inibizione mirate a bloccare CK2, al fine di ridurre selettivamente la sua attività nelle cellule tumorali e di produrre effetti cellulari che possono contrastare la trasformazione maligna. In particolare, abbiamo utilizzato: 1) CX-4945 e CX-5011, inibitori di CK2 ATP- competitivi (Pierre et al., 2011); 2) K137-E4, un inibitore bifunzionale progettato per competere simultaneamente con ATP e con il sito di legame per il peptide substrato di CK2; 3) CRIBI-300, un composto derivato da CIGB-300, progettato per impedire la fosforilazione di substrati specifici da parte di CK2 (Perea et al., 2004). Questi tre argomenti di ricerca sono riassunti di seguito. Viene presentato anche un quarto studio che ha riguardato un composto, TBID, sviluppato partendo da un inibitore di CK2, modificandolo per renderlo selettivo nei confronti di un'altra proteinchinasi, HIPK2.

Effetti degli inibitori di CK2 ATP-competitivi CX-4945 e CX-5011 in cellule resistenti all’apoptosi
Gli inibitori CX-4945 e CX-5011 (sviluppati dalla Cylene Pharmaceuticals) agiscono competendo con l’ATP per il legame nella tasca catalitica di CK2. Questi composti sono molto potenti e selettivi nell’inibire CK2 (Pierre et al., 2011; Battistutta et al., 2012), il CX-4945 in particolare ha mostrato buone proprietà farmacologiche ed è in sperimentazione clinica nell’uomo con promettenti risultati. Tuttavia, i composti CX non sono mai stati utilizzati in cellule resistenti all’apoptosi. In questo lavoro dimostriamo come CX-4945 e CX-5011 siano efficaci nel ridurre l’attività endogena di CK2 e nell’indurre apoptosi in diverse linee cellulari tumorali sensibili e resistenti all’apoptosi. Abbiamo inoltre trovato che le cellule resistenti che esprimono una pompa di estrusione dei farmaci, la P-gp, vengono rese sensibili a farmaci antitumorali convenzionali grazie all’uso di CX-4945. Infatti abbiamo trovato che l’accumulo di doxorubicina viene incrementato in cellule resistenti e che il trattamento combinato con CX-4945 e vinblastina produce effetti sinergici sulla morte cellulare. Pertanto, i nostri dati suggeriscono che gli inibitori CX possono essere considerati come una valida strategia terapeutica anche nei casi di resistenza farmacologica.
Effetti di inibitori di CK2 bifunzionali in cellule tumorali
Una nuova strategia per inibire CK2 è basata su composti definiti come inibitori bifunzionali o bisubstrato, disegnati per legarsi contemporaneamente ai siti di legame per l’ATP e per il substrato di CK2, con lo scopo di aumentarne la selettività per CK2. Tra questi composti il K137-E4 è stato recentemente sviluppato e caratterizzato in vitro nel nostro laboratorio: è stato dimostrato che è molto potente nell’inibire la CK2 ricombinante (IC50 = 0,025 uM) e che ha buona selettività. Nello studio presentato in questa tesi, ci siamo proposti di analizzare la possibilità di utilizzo di questo composto anche in cellule. Innanzitutto abbiamo dimostrato che il K137-E4 è in grado di inibire l’attività di CK2 nativa nei confronti di substrati cellulari. Tuttavia, questo si riferisce ad esperimenti in vitro, mentre quando abbiamo trattato le cellule con il K137-E4 non abbiamo osservato alcun effetto né sull’attività di CK2 né sulla vitalità cellulare. Abbiamo pertanto ipotizzato che il composto, essendo piuttosto idrofilico, non fosse in grado di attraversare la membrana cellulare. Sono tuttora in corso modifiche strutturali della molecola mirate ad aumentarne la permeabilità cellulare senza diminuirne significativamente la sua capacità inibitoria. Ad oggi, abbiamo pensato che il K137-E4, in virtù della sua impossibilità di attraversare la membrana plasmatica, può essere utile per studiare l’attività ectochinasica di CK2, cioè di quella porzione di enzima che risiede sulla superficie esterna delle cellule (Kubler et al., 1989). Abbiamo infatti dimostrato che questo composto è capace di inibire CK2 ectochinasica, ma che ciò non ha alcun effetto sulla vitalità cellulare né di cellule tumorali né di cellule non tumorali. Questa scoperta, assieme all’osservazione che l’attività ectochinasica di CK2 sembra essere simile in cellule tumorali e non, suggerisce che la CK2 ectochinasica non è implicata nella sopravvivenza cellulare e negli eventi correlati alla tumorigenesi.
Effetti in vitro e in cellule di peptidi mirati a legare substrati di CK2
Un nuovo approccio recentemente introdotto per colpire CK2 è basato sullo sviluppo di un peptide ciclico, chiamato CIGB-300, che interferisce con la fosforilazione di specifici substrati di CK2 piuttosto che inibire con l’enzima per se (Perea et al., 2004). CIGB-300 è già impiegato in studi clinici (Perea et al., 2011), tuttavia il suo meccanismo d’azione è solo parzialmente conosciuto. Abbiamo dunque sfruttato un nuovo peptide sintetico, chiamato CRIBI-300, con lo stesso dominio funzionale del CIGB-300, e abbiamo effettuato studi in vitro ed in cellule, comparandolo con il CIGB-300 e altri suoi derivati. Abbiamo scoperto che l’attività di CK2 in vitro può essere influenzata dal peptide CRIBI-300, ma con effetti differenti a seconda del tipo di substrato utilizzato: abbiamo osservato inibizione solo per quei substrati la cui fosforilazione da parte di CK2 è strettamente dipendente dalla presenza della subunità regolatoria b, mentre troviamo stimolazione da parte del CRIBI-300 nei confronti di substrati che sono fosforilati preferenzialmente dalla subunità catalitica a. Questi dati suggeriscono che il CRIBI-300 potrebbe interferire con la struttura dell’oloenzima CK2, dando luogo ad una conformazione tetramerica instabile e non funzionale e impedendo la fosforilazione di substrati b-dipendenti.
Anche in esperimenti di trattamento cellulare, abbiamo trovato che CRIBI-300 induce una forte riduzione dell’attività cellulare di CK2, che è però accompagnata da una precoce e rapida perdita della quantità proteica di CK2. In parallelo, CRIBI-300 induce anche morte cellulare, ma non per apoptosi. Inoltre, abbiamo osservato diminuzione delle quantità di altre proteine, oltre a CK2, e un’alterazione dell’attività dei sistemi proteolitici con l’attivazione di proteasi lisosomiali e il blocco del proteasoma. Tutti questi effetti appaiono più evidenti in cellule tumorali che in cellule non tumorali.
Abbiamo poi analizzato gli effetti di derivati peptidici del CRIBI-300, con sostituzioni di singoli aminoacidi o con sequenze diverse. E’ interessante il fatto che abbiamo trovato che la sequenza Tat (la porzione del CRIBI-300 introdotta per renderlo permeabile alla cellula (Holm et al., 2006)) è essenziale per la sua attività su CK2 in vitro e in cellula, ma non è sufficiente di per se dal momento che specifici amminoacidi nella parte funzionale del CRIBI-300 (la sequenza non corrispondente a Tat) risulta essere cruciale per produrre gli effetti. Dei molti effetti causati dal CRIBI-300, abbiamo cercato di capire quali fossero mediati dalla sua azione su CK2. Abbiamo trovato che la riduzione dell’espressione di CK2 (ottenuta mediante esperimenti di “RNA interference”) attenua alcuni degli effetti del CRIBI-300, sebbene non tutti. Inoltre, quelle modifiche della sequenza del CRIBI-300 che impediscono i suoi effetti in vitro su CK2 sono anche capaci di ridurne gli effetti a livello cellulare. Possiamo perciò concludere che CK2 è sicuramente uno dei più importanti bersagli di CRIBI-300. Tuttavia altri meccanismi d’azione di questo composto devono esistere per spiegarne tutti gli effetti osservati, e ciò suggerisce quindi che un’estrema cautela è richiesta per l’utilizzo di questo composto.
Effetti dell’inibitore TBID sull’attivita’ cellulare di HIPK2
Uno studio collaterale presentato in questa tesi riguarda il composto TBID, che deriva da un inibitore di CK2, il TBI, ma che è stato modificato nella struttura per renderlo selettivo nei confronti di un’altra chinasi, HIPK2 (Homeodomain-interacting protein kinase 2), una Ser/Thr chinasi che controlla la proliferazione e sopravvivenza cellulare (D’Orazi et al., 2012) il cui studio è stato rallentato dalla mancanza di inibitori specifici capaci di svelarne le funzioni cellulari. TBID è un inibitore ATP-competitivo molto potente nei confronti di HIPK2 in vitro (IC50 = 0,33 uM) e molto selettivo. In questa tesi mostriamo che TBID è anche in grado di entrare nelle cellule, dimostrando che inibisce l’attività di HIPK2 intracellulare e riduce la fosforilazione della Ser46 di p53, un sito fosforilato da HIPK2. Dal momento che TBID non è citotossico nelle condizioni utilizzate per analizzarne gli effetti sull’attività di HIPK2 cellulare, proponiamo TBID come l’unico strumento attualmente disponibile per inibire HIPK2 in cellule.
I risultati presentati in questa tesi dimostrano che l’inibizione di chinasi rappresenta uno strumento estremamente versatile per l’utilizzo nelle cellule, sia per analizzare il ruolo di una specifica chinasi, sia per bloccarne una non desiderata iperattività. In particolare, nel caso di inibitori di CK2 abbiamo analizzato diverse strategie. Sebbene al momento la più efficace e convincente rimanga quella rappresentata dai classici composti ATP-competitivi, abbiamo presentato altri approcci che, pur necessitando di ulteriori studi, potranno in futuro dimostrarsi promettenti in termini di aumentata specificità o di maggiore selettività degli effetti prodotti.

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Tipo di EPrint:Tesi di dottorato
Relatore:Ruzzene, Maria
Dottorato (corsi e scuole):Ciclo 26 > Scuole 26 > BIOSCIENZE E BIOTECNOLOGIE > BIOCHIMICA E BIOFISICA
Data di deposito della tesi:31 Gennaio 2014
Anno di Pubblicazione:31 Gennaio 2014
Parole chiave (italiano / inglese):Fosforilazione proteica/ Protein phosphorylation Protein chinasi CK2/Protein kinase CK2 Inibitori di CK2/CK2 inhibitors Protein chinasi HIPK2/Protein kinasi HIPK2
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/10 Biochimica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:6376
Depositato il:31 Ott 2014 13:30
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Le url contenute in alcuni riferimenti sono raggiungibili cliccando sul link alla fine della citazione (Vai!) e tramite Google (Ricerca con Google). Il risultato dipende dalla formattazione della citazione.

Amaravadi, R., and Thompson, C.B. The survival kinases Akt and Pim as potential Cerca con Google

pharmacological targets. J. Clin. Invest. 2005; 115, 2618–2624. Cerca con Google

Anastassiadis T, Deacon S, Devarajan K, Ma H, Peterson J. Comprehensive assay of kinase Cerca con Google

catalytic activity reveals features of kinase inhibitor selectivity. Nature biotechnology. Cerca con Google

2011; 29 (11): 1039–1045. Cerca con Google

Andersen, K.M., Hofmann, K., and Hartmann-Petersen, R. Ubiquitin-binding proteins: Cerca con Google

similar, but different. Essays Biochem. 2005; 41, 49–67. Cerca con Google

Antonelli, M., Daniotti, J. L., Rojo, D., Allende, C. C. and Allende, J. E. Cloning, expression Cerca con Google

and properties of the alpha subunit of casein kinase 2 from zebrafish (Danio rerio). Cerca con Google

European Journal of Biochemistry. 1996; 241 (1), pp. 272–279. Cerca con Google

Aparicio, J.G., and Applebury, M.L. The photoreceptor guanylate cyclase is an Cerca con Google

autophosphorylating protein kinase. J. Biol. Chem. 1996; 271, 27083–27089. Cerca con Google

Arrigoni, G., Pagano, M. A., Sarno, S., Cesaro, L., James, P. and Pinna, L. A. Mass Cerca con Google

spectrometry analysis of a protein kinase CK2 beta subunit interactome isolated from Cerca con Google

mouse brain by affinity chromatography. The Journal of Proteome Research, 2008; 7 Cerca con Google

(3), pp. 990–1000. Cerca con Google

Bachelot T., C. Bourgier, C. Cropet et al., Randomized phase II trial of everolimus in Cerca con Google

combination with tamoxifen in patients with hormone receptor-positive, human Cerca con Google

epidermal growth factor receptor 2-negative metastatic breast cancer with prior Cerca con Google

exposure to aromatase inhibitors: a GINECO study. Journal of Clinical Oncology, Cerca con Google

2012; vol. 30, no. 22, pp. 2718–2724 Cerca con Google

Baker E. K., R. W. Johnstone, J. R. Zalcberg, and A. El-Osta. Epigenetic changes to the Cerca con Google

MDR1 locus in response to chemotherapeutic drugs. Oncogene, 2005; vol. 24, no. 54, Cerca con Google

pp. 8061–8075, Cerca con Google

Bain J, Plater L, Elliott M, Shpiro N, Hastie C, Mclauchlan H, Klevernic I, Arthur J, Alessi Cerca con Google

D, Cohen P. The selectivity of protein kinase inhibitors: a further update. Biochem. J. Cerca con Google

2007; 408: 297–315. Cerca con Google

182 Cerca con Google

Baselga J., M. Campone, M. Piccart et al., Everolimus in postmenopausal Cerca con Google

hormone-receptor-positive advanced breast cancer. New England Journal of Medicine Cerca con Google

2012; vol. 366, no. 6, pp.520–529 Cerca con Google

Battistutta R, Cozza G, Pierre F, Papinutto E, Lolli G, Sarno S, O’Brien S, Siddiqui-Jain A, Cerca con Google

Haddach M, Anderes K, Others. Unprecedented selectivity and structural determinants Cerca con Google

of a new class of protein kinase CK2 inhibitors in clinical trials for the treatment of Cerca con Google

cancer. Biochemistry. 2011; 50 (39): 8478–8488. Cerca con Google

Battistutta R, De Moliner E, Sarno S, Zanotti G, Pinna L. Structural features underlying Cerca con Google

selective inhibition of protein kinase CK2 by ATP site-directed Cerca con Google

tetrabromo-2-benzotriazole. Protein Science. 2001; 10 (11): 2200–2206. Cerca con Google

Battistutta R, Mazzorana M, Cendron L, Bortolato A, Sarno S, Kazimierczuk Z, Zanotti G, Cerca con Google

Moro S, Pinna L. The ATP-Binding Site of Protein Kinase CK2 Holds a Positive Cerca con Google

Electrostatic Area and Conserved Water Molecules. Chembiochem. 2007; 8 (15): Cerca con Google

1804–1809. Cerca con Google

Berman H, Battistuz T, Bhat T, Bluhm W, Bourne P, Burkhardt K, Feng Z, Gillil, Iype L, Cerca con Google

Jain S, Others. The protein data bank. Acta Crystallographica Section D: Biological Cerca con Google

Crystallography. 2002; 58 (6): 899–907. Cerca con Google

Birnbaum M, Glover C. The phosphotransferase activity of casein kinase II is required for its Cerca con Google

physiological function in vivo. Biochemical and biophysical research communications. Cerca con Google

1991; 181 (2): 524–528. Cerca con Google

Blagden S, Bono J. Drugging cell cycle kinases in cancer therapy. Current drug targets. Cerca con Google

2005; 6 (3): 325–335. Cerca con Google

Bliesath, J., Huser, N., Omori, M., Bunag, D., Proffitt, C., Streiner, N., Ho, C., Siddiqui-Jain, Cerca con Google

A., O’Brien, S.E., Lim, J.K.C., et al. Combined inhibition of EGFR and CK2 augments Cerca con Google

the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Cerca con Google

Lett. 2012 322, 113–118. Cerca con Google

Blume-Jensen P, Hunter T. Oncogenic kinase signalling. Nature. 2001; 411 (6835): 355–365. Cerca con Google

183 Cerca con Google

Bohana-Kashtan O, Pinna LA, Fishelson Z. Extracellular phosphorylation of C9 by protein Cerca con Google

kinase CK2 regulates complement-mediated lysis. Eur J Immunol 2005;35:1939 –1948 Cerca con Google

Boldyreff, B., Meggio, F., Pinna, L. A. and Issinger, O. G. Reconstitution of normal and Cerca con Google

hyperactivated forms of casein kinase-2 by variably mutated beta subunits. Cerca con Google

Biochemistry, 1993; 32 (47), pp. 12672–12677. Cerca con Google

Boldyreff, B., Meggio, F., Pinna, L. A. and Issinger, O. Efficient autophosphorylation and Cerca con Google

phosphorylation of the beta-subunit by casein kinase-2 require the integrity of an acidic Cerca con Google

cluster 50 residues downstream from the phosphoacceptor site. Journal of Biological Cerca con Google

Chemistry, 1994; 269 (7), pp. 4827–4831. Cerca con Google

Borgo, C., Cesaro, L., Salizzato, V., Ruzzene, M., Massimino, M.L., Pinna, L.A., and Cerca con Google

Donella-Deana, A. Aberrant signalling by protein kinase CK2 in imatinib-resistant Cerca con Google

chronic myeloid leukaemia cells: biochemical evidence and therapeutic perspectives. Cerca con Google

Mol Oncol 2013; 7, 1103–1115. Cerca con Google

Borst P, Evers R, Kool M, Wijnholds J. A family of drug transporters: the multidrug Cerca con Google

resistance-associated proteins. Journal of the National Cancer Institute. 2000; 92 (16): Cerca con Google

1295–1302. Cerca con Google

Brault, L., Gasser, C., Bracher, F., Huber, K., Knapp, S., and Schwaller, J. PIM Cerca con Google

serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies Cerca con Google

and solid cancers. Haematologica 2010; 95, 1004–1015. Cerca con Google

Breivik, J. The evolutionary origin of genetic instability in cancer development. Semin. Cerca con Google

Cancer Biol. 2005; 15, 51–60. Cerca con Google

Brognard J, Hunter T. Protein kinase signaling networks in cancer. Current opinion in Cerca con Google

genetics & development. 2011; 21 (1): 4–11. Cerca con Google

Buontempo, F., Orsini, E., Martins, L.R., Antunes, I., Lonetti, A., Chiarini, F., Tabellini, G., Cerca con Google

Evangelisti, C., Evangelisti, C., Melchionda, F., et al. Cytotoxic activity of the casein Cerca con Google

kinase 2 inhibitor CX-4945 against T-cell acute lymphoblastic leukemia: targeting the Cerca con Google

unfolded protein response signaling. Leukemia. 2013 Cerca con Google

184 Cerca con Google

Calzado M, Renner F, Roscic A, Schmitz M. HIPK2, a versatile switchboard regulating the Cerca con Google

transcription machinery and cell death. Cell Cycle. 2007; 6 (2): 139–143. Cerca con Google

Canton, D., Zhang, C. And Litchfield, D. Assembly of protein kinase CK2: investigation of Cerca con Google

complex formation between catalytic and regulatory subunits using a Cerca con Google

zinc-finger-deficient mutant of CK2 beta . Biochem. J, 2001; 358 pp. 87–94. Cerca con Google

Caulin, A.F., and Maley, C.C. Peto’s Paradox: evolution’s prescription for cancer prevention. Cerca con Google

Trends Ecol. Evol. (Amst.) 2011; 26, 175–182. Cerca con Google

Channavajhala P., D.C. Seldin, Functional interaction of protein kinase CK2 and c-Myc in Cerca con Google

lymphomagenesis. Oncogene 2002; 21 5280–5288. Cerca con Google

Chantalat, L., Leroy, D., Filhol, O., Nueda, A., Benitez, M. J., Chambaz, E. M., Cochet, C. Cerca con Google

and Dideberg, O. Crystal structure of the human protein kinase CK2 regulatory subunit Cerca con Google

reveals its zinc finger-mediated dimerization. The EMBO journal, 1999; 18 (11), pp. Cerca con Google

2930–2940. Cerca con Google

Chekhun V. F., N. Y. Lukyanova, O. Kovalchuk, V. P. Tryndyak, and I. P. Pogribny, Cerca con Google

Epigenetic profiling of multidrugresistant human MCF-7 breast adenocarcinoma cells Cerca con Google

reveals novel hyper- and hypomethylated targets. Molecular Cancer Therapeutics. Cerca con Google

2007;vol. 6, no. 3, pp. 1089–1098 Cerca con Google

Chen, M., Li, D., Krebs, E. G. and Cooper, J. A. The casein kinase II beta subunit binds to Cerca con Google

Mos and inhibits Mos activity. Molecular and cellular biology, 1997; 17 (4), pp. Cerca con Google

1904–1912. Cerca con Google

Chua, P.C.P., F.; Whitten, J.P. , Serine-threonine protein kinase and PARP modulators. Cerca con Google

Patent number WO 2008/028168 A2, 2008. Cerca con Google

Cohen P. Protein kinases: the major drug targets of the twenty-first century?. Nature Reviews Cerca con Google

Drug Discovery. 2002; 1 (4): 309–315. Cerca con Google

Cohen P. The regulation of protein function by multisite phosphorylation: a 25 year update. Cerca con Google

Trends in biochemical sciences. 2000; 25 (12): 596–601. Cerca con Google

185 Cerca con Google

Colaert N, Helsens K, Martens L, V, Ekerckhove J, Gevaert K. Improved visualization of Cerca con Google

protein consensus sequences by iceLogo. Nature methods. 2009; 6 (11): 786–787. Cerca con Google

Cozza G, Bonvini P, Zorzi E, Poletto G, Pagano M, Sarno S, Donella-Deana A, Zagotto G, Cerca con Google

Rosolen A, Pinna L, Others. Identification of ellagic acid as potent inhibitor of protein Cerca con Google

kinase CK2: a successful example of a virtual screening application. Journal of Cerca con Google

medicinal chemistry. 2006; 49 (8): 2363–2366. Cerca con Google

Cozza, G., Bortolato, A. and Moro, S. How druggable is protein kinase CK2?. Medicinal Cerca con Google

research reviews, 2010; 30 (3), pp. 419–462. Cerca con Google

Cozza G, Gianoncelli A, Bonvini P, Zorzi E, Pasquale R, Rosolen A, Pinna L, Meggio F, Cerca con Google

Zagotto G, Moro S. Urolithin as a converging scaffold linking ellagic acid and coumarin Cerca con Google

analogues: design of potent protein kinase CK2 inhibitors. ChemMedChem. 2011; 6 Cerca con Google

(12): 2273–2286. Cerca con Google

Cozza G, Girardi C, Ranchio A, Lolli G, Sarno S, Orzeszko A, Kazimierczuk Z, Battistutta Cerca con Google

R, Ruzzene M, Pinna L. Cell-permeable dual inhibitors of protein kinases CK2 and Cerca con Google

PIM-1: structural features and pharmacological potential. Cellular and Molecular Life Cerca con Google

Sciences. 2014;: 1–13. Cerca con Google

Cozza G, Mazzorana M, Papinutto E, Bain J, Elliott M, Di Maira G, Gianoncelli A, Pagano Cerca con Google

M, Sarno S, Ruzzene M, Others. Quinalizarin as a potent, selective and cell-permeable Cerca con Google

inhibitor of protein kinase CK2. Biochem. J. 2009; 421: 387–395. Cerca con Google

Cozza G, Meggio F, Moro S. The dark side of protein kinase CK2 inhibition. Current Cerca con Google

medicinal chemistry. 2011; 18 (19): 2867–2884. Cerca con Google

Cozza G, Pinna L, Moro S. Kinase CK2 Inhibition: An Update. Current medicinal chemistry. Cerca con Google

2013; 20 (5): 671–693. Cerca con Google

Crespi B, Summers K. Evolutionary biology of cancer. Trends in ecology & evolution. 2005; Cerca con Google

20 (10): 545–552. Cerca con Google

D'orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Cerca con Google

186 Cerca con Google

Marchetti A, Del Sal G, Others. Homeodomain-interacting protein kinase-2 Cerca con Google

phosphorylates p53 at Ser 46 and mediates apoptosis. Nature cell biology. 2001; 4 (1): Cerca con Google

11–19. Cerca con Google

Davies S, Reddy H, Caivano M, Cohen P. Specificity and mechanism of action of some Cerca con Google

commonly used protein kinase inhibitors. Biochem. J. 2000; 351: 95–105. Cerca con Google

De Moliner E, Moro S, Sarno S, Zagotto G, Zanotti G, Pinna L, Battistutta R. Inhibition of Cerca con Google

Protein Kinase CK2 by Anthraquinone-related Compounds a structural insight. Journal Cerca con Google

of Biological Chemistry. 2003; 278 (3): 1831–1836. Cerca con Google

Desagher, S., Osen-Sand, A., Montessuit, S., Magnenat, E., Vilbois, F., Hochmann, A., Cerca con Google

Journot, L., Antonsson, B. and Martinou, J. C. Phosphorylation of bid by casein kinases Cerca con Google

I and II regulates its cleavage by caspase 8. Mol. Cell 2001;8, 601– 611 Cerca con Google

Di Maira G, Brustolon F, Bertacchini J, Tosoni K, Marmiroli S, Pinna L, Ruzzene M. Cerca con Google

Pharmacological inhibition of protein kinase CK2 reverts the multidrug resistance Cerca con Google

phenotype of a CEM cell line characterized by high CK2 level. Oncogene. 2007; 26 Cerca con Google

(48): 6915–6926. Cerca con Google

Di Stefano V, Bl, Ino G, Sacchi A, Soddu S, D'orazi G. HIPK2 neutralizes MDM2 inhibition Cerca con Google

rescuing p53 transcriptional activity and apoptotic function. Oncogene. 2004; 23 (30): Cerca con Google

5185–5192. Cerca con Google

Dobrowolska, G., Meggio, F., Szczegielniak, J., Muszynska, G. And Pinna, L. A. Cerca con Google

Purification and characterization of maize seedling casein kinase IIB, a monomeric Cerca con Google

enzyme immunologically related to the alpha subunit of animal casein kinase-2. Cerca con Google

European journal of biochemistry, 1992; 204 (1), pp. 299–303. Cerca con Google

Dobrowolska G, Muszynska G, Shugar D. Benzimidazole nucleoside analogues as inhibitors Cerca con Google

of plant (maize seedling) casein kinases. Biochimica et Biophysica Acta (BBA)-Protein Cerca con Google

Structure and Molecular Enzymology. 1991; 1080 (3): 221–226. Cerca con Google

Enkvist E, Viht K, Bischoff N, Vahter J, Saaver S, Raidaru G, Issinger O, Niefind K, Uri A. Cerca con Google

A subnanomolar fluorescent probe for protein kinase CK2 interaction studies. Organic Cerca con Google

187 Cerca con Google

& Biomolecular Chemistry. 2012; 10 (43): 8645–8653. Cerca con Google

Escargueil, A. E., Plisov, S. Y., Filhol, O., Cochet, C. and Larsen, A. K. Mitotic Cerca con Google

phosphorylation of DNA topoisomerase II alpha by protein kinase CK2 creates the Cerca con Google

MPM-2 phosphoepitope on ser-1469. J. Biol. Chem. 2000; 275, 34710–34718 Cerca con Google

Fracasso P. M., P. Westervelt, C. L. Fears et al., Phase I study of paclitaxel in combination Cerca con Google

with a multidrug resistance modulator, PSC 833 (Valspodar), in refractory Cerca con Google

malignancies, Journal of Clinical Oncology, 2000; vol. 18, no. 5, pp. 1124–1134 Cerca con Google

Fritz, G., Issinger, O.-G., and Olsen, B.B. Selectivity analysis of protein kinase CK2 Cerca con Google

inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses. Int. J. Cerca con Google

Oncol. 2009; 35, 1151–1157. Cerca con Google

Fusco A, Fedele M. Roles of HMGA proteins in cancer. Nature Reviews Cancer. 2007; 7 Cerca con Google

(12): 899–910. Cerca con Google

Gianoncelli A, Cozza G, Orzeszko A, Meggio F, Kazimierczuk Z, Pinna L. Cerca con Google

Tetraiodobenzimidazoles are potent inhibitors of protein kinase CK2. Bioorganic & Cerca con Google

medicinal chemistry. 2009; 17 (20): 7281–7289. Cerca con Google

Gietz, R. D., Graham, K. C. and Litchfield, D. W. Interactions between the subunits of casein Cerca con Google

kinase II. Journal of Biological Chemistry, 1995; 270 (22), pp. 13017–13021. Cerca con Google

Glavy J, Horwitz S, Orr G. Identification of the in vivo phosphorylation sites for Cerca con Google

acidic-directed kinases in murine mdr1b P-glycoprotein. Journal of Biological Cerca con Google

Chemistry. 1997; 272 (9): 5909–5914. Cerca con Google

Glover C. A filamentous form of Drosophila casein kinase II. Journal of Biological Cerca con Google

Chemistry. 1986; 261 (30): 14349–14354. Cerca con Google

Glover III, C. V. On the physiological role of casein kinase II in Saccharomyces cerevisiae. Cerca con Google

Prog. Nucleic Acid Res. 1998; Mol. Biol. 59, 95– 133 Cerca con Google

Golub A, Bdzhola V, Kyshenia Y, Sapelkin V, Prykhod’Ko A, Kukharenko O, Ostrynska O, Cerca con Google

Yarmoluk S. Structure-based discovery of novel flavonol inhibitors ofYakovenko O, Bdzhola V, Sapelkin V, Zien P, Yarmoluk S. Evaluation of Cerca con Google

3-Carboxy-4 (1 H)-quinolones as Inhibitors of Human Protein Kinase CK2. Journal of Cerca con Google

medicinal chemistry. 2006; 49 (22): 6443–6450. Cerca con Google

Golub A, Yakovenko O, Prykhod'ko A, Lukashov S, Bdzhola V, Yarmoluk S. Evaluation of Cerca con Google

4, 5, 6, 7-tetrahalogeno-isoindole-1, 3 diones as inhibitors of human protein kinase Cerca con Google

CK2. Biochimica et Biophysica Acta (BBA)-Proteins \& Proteomics. 2008; 1784 (1): Cerca con Google

143–149. Cerca con Google

Gotz C, Gratz A, Kucklaender U, Jose J. TF—A novel cell-permeable and selective inhibitor Cerca con Google

of human protein kinase CK2 induces apoptosis in the prostate cancer cell line LNCaP. Cerca con Google

Biochimica et Biophysica Acta (BBA)-General Subjects. 2012; 1820 (7): 970–977. Cerca con Google

Gottesman M. Cancer gene therapy: an awkward adolescence. Cancer gene therapy. 2003; Cerca con Google

10 (7): 501–508. Cerca con Google

Greaves M. Darwinian medicine: a case for cancer. Nature Reviews Cancer. 2007; 7 (3): Cerca con Google

213–221. Cerca con Google

Guerra B, Issinger O. Protein kinase CK2 in human diseases. Current medicinal chemistry. Cerca con Google

2008; 15 (19): 1870–1886. Cerca con Google

Haddach, M., Pierre, F., Regan, C.F., Borsan, C., Michaux, J., Stefan, E., Kerdoncuff, P., Cerca con Google

Schwaebe, M.K., Chua, P.C., Siddiqui-Jain, A., et al. Synthesis and SAR of inhibitors Cerca con Google

of protein kinase CK2: novel tricyclic quinoline analogs. Bioorg. Med. Chem. Lett. 2012 Cerca con Google

22, 45–48. Cerca con Google

Hall M, H, Ley M, Gottesman M. Is resistance useless? Multidrug resistance and collateral Cerca con Google

sensitivity. Trends in pharmacological sciences. 2009; 30 (10): 546–556. Cerca con Google

Hanahan D., Weinberg, R.A. The hallmarks of cancer, Cell 2000; 100 57–70 Cerca con Google

Hanks S, Hunter T. Protein kinases 6. The eukaryotic protein kinase superfamily: kinase Cerca con Google

(catalytic) domain structure and classification. The FASEB Journal. 1995; 9 (8): Cerca con Google

189 Cerca con Google

576–596. Cerca con Google

Harvey E, Li N, Ramji D. Critical Role for Casein Kinase 2 and Phosphoinositide-3-Kinase Cerca con Google

in the Interferon- gamma –Induced Expression of Monocyte Chemoattractant Protein-1 Cerca con Google

and Other Key Genes Implicated in Atherosclerosis. Arteriosclerosis, thrombosis, and Cerca con Google

vascular biology. 2007; 27 (4): 806–812. Cerca con Google

Hauber, J., Malim, M.H., and Cullen, B.R. Mutational analysis of the conserved basic Cerca con Google

domain of human immunodeficiency virus tat protein. J. Virol. 1989 63, 1181–1187. Cerca con Google

Heppner G, Dexter D, Denucci T, Miller F, Calabresi P. Heterogeneity in drug sensitivity Cerca con Google

among tumor cell subpopulations of a single mammary tumor. Cancer research. 1978; Cerca con Google

38 (11 Part 1): 3758–3763. Cerca con Google

Hipfner D, Deeley R, Cole S. Structural, mechanistic and clinical aspects of MRP1. Cerca con Google

Biochimica et Biophysica Acta (BBA)-Biomembranes. 1999; 1461 (2): 359–376. Cerca con Google

Hofmann T, Moller A, Sirma H, Zentgraf H, Taya Y, Droge W, Will H, Schmitz M. Cerca con Google

Regulation of p53 activity by its interaction with homeodomain-interacting protein Cerca con Google

kinase-2. Nature cell biology. 2001; 4 (1): 1–10. Cerca con Google

Holm, T., Johansson, H., Lundberg, P., Pooga, M., Lindgren, M., and Langel, U. Studying Cerca con Google

the uptake of cell-penetrating peptides. Nat Protoc 2006 1, 1001–1005. Cerca con Google

Hou Z, Nakanishi I, Kinoshita T, Takei Y, Yasue M, Misu R, Suzuki Y, Nakamura S, Kure Cerca con Google

T, Ohno H, Others. Structure-based design of novel potent protein kinase CK2 (CK2) Cerca con Google

inhibitors with phenyl-azole scaffolds. Journal of Medicinal Chemistry. 2012; 55 (6): Cerca con Google

2899–2903. Cerca con Google

Hubert, A., Paris, S., Piret, J.-P., Ninane, N., Raes, M., and Michiels, C. Casein kinase 2 Cerca con Google

inhibition decreases hypoxia-inducible factor-1 activity under hypoxia through elevated Cerca con Google

p53 protein level. J. Cell. Sci. 2006 119, 3351–3362. Cerca con Google

Hung, M.-S., Xu, Z., Chen, Y., Smith, E., Mao, J.-H., Hsieh, D., Lin, Y.-C., Yang, C.-T., Cerca con Google

Jablons, D.M., and You, L. Hematein, a casein kinase II inhibitor, inhibits lung cancer Cerca con Google

190 Cerca con Google

tumor growth in a murine xenograft model. Int. J. Oncol. 2013. 43, 1517–1522. Cerca con Google

Ishikawa T, Ali-Osman F. Glutathione-associated cis-diamminedichloroplatinum (II) Cerca con Google

metabolism and ATP-dependent efflux from leukemia cells. Molecular characterization Cerca con Google

of glutathione-platinum complex and its biological significance. Journal of Biological Cerca con Google

Chemistry. 1993; 268 (27): 20116–20125. Cerca con Google

Jedlitschky G, Leier I, Buchholz U, Barnouin K, Kurz G, Keppler D. Transport of Cerca con Google

glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate Cerca con Google

export pump. Cancer Research. 1996; 56 (5): 988–994. Cerca con Google

Johnson L, Lewis R. Structural basis for control by phosphorylation. Chemical reviews. Cerca con Google

2001; 101 (8): 2209–2242. Cerca con Google

Jones, S.W., Christison, R., Bundell, K., Voyce, C.J., Brockbank, S.M.V., Newham, P., and Cerca con Google

Lindsay, M.A. Characterisation of cell-penetrating peptide-mediated peptide delivery. Cerca con Google

Br. J. Pharmacol. 2005 145, 1093–1102. Cerca con Google

Kaplan, I.M., Wadia, J.S., and Dowdy, S.F. Cationic TAT peptide transduction domain Cerca con Google

enters cells by macropinocytosis. J Control Release 2005 102, 247–253. Cerca con Google

Kasahara K, Fujiwara Y, Nishio K, Ohmori T, Sugimoto Y, Komiya K, Matsuda T, Saijo N. Cerca con Google

Metallothionein content correlates with the sensitivity of human small cell lung cancer Cerca con Google

cell lines to cisplatin. Cancer research. 1991; 51 (12): 3237–3242. Cerca con Google

Kawase M, Sakagami H, Hashimoto K, Tani S, Hauer H, Chatterjee S. Structure-cytotoxic Cerca con Google

activity relationships of simple hydroxylated coumarins. Anticancer research. 2003; 23 Cerca con Google

(4): 3243–3246. Cerca con Google

Kim, G.S., Jung, J.E., Niizuma, K., and Chan, P.H. CK2 is a novel negative regulator of Cerca con Google

NADPH oxidase and a neuroprotectant in mice after cerebral ischemia. J. Neurosci. Cerca con Google

2009; 29, 14779–14789. Cerca con Google

Kim, J., and Kim, S.H. Druggability of the CK2 inhibitor CX-4945 as an anticancer drug and Cerca con Google

beyond. Arch. Pharm. Res. 2012; 35, 1293–1296. Cerca con Google

191 Cerca con Google

Kim, J.S., Eom, J.I., Cheong, J.-W., Choi, A.J., Lee, J.K., Yang, W.I., and Min, Y.H. Protein Cerca con Google

kinase CK2alpha as an unfavorable prognostic marker and novel therapeutic target in Cerca con Google

acute myeloid leukemia. Clin. Cancer Res. 2007; 13, 1019–1028. Cerca con Google

Kim Y, Choi C, Lee S, Conti M, Kim Y. Homeodomain-interacting protein kinases, a novel Cerca con Google

family of co-repressors for homeodomain transcription factors. Journal of Biological Cerca con Google

Chemistry. 1998; 273 (40): 25875–25879. Cerca con Google

Kitchen, D.B., Decornez, H., Furr, J.R., and Bajorath, J. Docking and scoring in virtual Cerca con Google

screening for drug discovery: methods and applications. Nat Rev Drug Discov 2004; 3, Cerca con Google

935–949. Cerca con Google

Kikkawa U, Mann S, Firtel R, Hunter T. Molecular cloning of casein kinase II alpha subunit Cerca con Google

from Dictyostelium discoideum and its expression in the life cycle. Molecular and Cerca con Google

cellular biology. 1992; 12 (12): 5711–5723. Cerca con Google

Kobe B, Kemp B. Active site-directed protein regulation. Nature. 1999; 402 (6760): Cerca con Google

373–376. Cerca con Google

Koga, H., and Cuervo, A.M. Chaperone-mediated autophagy dysfunction in the pathogenesis Cerca con Google

of neurodegeneration. Neurobiol. Dis. 2011; 43, 29–37. Cerca con Google

Konig J, Rost D, Cui Y, Keppler D. Characterization of the human multidrug resistance Cerca con Google

protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology. Cerca con Google

1999; 29 (4): 1156–1163. Cerca con Google

Knighton D, Zheng J, Ten Eyck L, Xuong N, Taylor S, Sowadski J. Structure of a peptide Cerca con Google

inhibitor bound to the catalytic subunit of cyclic adenosine monophosphate-dependent Cerca con Google

protein kinase. Science. 1991; 253 (5018): 414–420. Cerca con Google

Krek, W., Maridor, G. and Nigg, E. Casein kinase II is a predominantly nuclear enzyme. The Cerca con Google

Journal of cell biology, 1992; 116 (1), pp. 43–55. Cerca con Google

Krippner-Heidenreich, A., Talanian, R. V., Sekul, R., Kraft, R., Thole, H., Ottleben, H. and Cerca con Google

Luscher, B. Targeting of the transcription factor Max during apoptosis : Cerca con Google

192 Cerca con Google

phosphorylation-regulated cleavage by caspase-5 at an unusual glutamic acid residue in Cerca con Google

position P1. Biochem. J. 2001; 358, 705– 715 Cerca con Google

Kubler D, Pyerin W, Burow E, Kinzel V. Substrate-effected release of surfacelocated protein Cerca con Google

kinase from intact cells. Proc Natl Acad Sci USA 1983; 80:4021–4025. Cerca con Google

Lacy, A., and O’Kennedy, R. Studies on coumarins and coumarin-related compounds to Cerca con Google

determine their therapeutic role in the treatment of cancer. Curr. Pharm. Des. 2004 10, Cerca con Google

3797–3811. Cerca con Google

Laudet B, Moucadel V, Prudent R, Filhol O, Wong Y, Royer D, Cochet C. Identification of Cerca con Google

chemical inhibitors of protein-kinase CK2 subunit interaction. Molecular and cellular Cerca con Google

biochemistry. 2008; 316 (1-2): 63–69. Cerca con Google

Le Coutre J, Kaback H. Structure–function relationships of integral membrane proteins: Cerca con Google

membrane transporters vs channels. Peptide Science. 2000; 55 (4): 297–307. Cerca con Google

Leary A. F., S. Drury, S.Detre et al., Lapatinib restores hormone sensitivity with differential Cerca con Google

effects on estrogen receptor signaling in cell models of human epidermal growth factor Cerca con Google

receptor 2-negative breast cancer with acquired endocrine resistance. Clinical Cancer Cerca con Google

Research, 2010; vol. 16, no. 5, pp. 1486–1497 Cerca con Google

Leroy, D., Herich'E, J., Filhol, O., Chambaz, E. M. and Cochet, C. Binding of polyamines to Cerca con Google

an autonomous domain of the regulatory subunit of protein kinase CK2 induces a Cerca con Google

conformational change in the holoenzyme A proposed role for the kinase stimulation. Cerca con Google

Journal of Biological Chemistry, 1997; 272 (33), pp. 20820–20827. Cerca con Google

Li P., Li J., Muller E., Otto A., Dietz R. and von Harsdorf, R. Phosphorylation by protein Cerca con Google

kinase CK2. A signaling switch for the caspase-inhibiting protein ARC. Mol. Cell 2002; Cerca con Google

10, 247– 258 Cerca con Google

Li, X., Shi, X., Liang, D.-Y., and Clark, J.D. Spinal CK2 regulates nociceptive signaling in Cerca con Google

models of inflammatory pain. Pain, 2005; 115, 182–190. Cerca con Google

Li X, Wu L, Ying S, Chang C, He Q, Pu Q. Differentiation and hematopoietic-support of Cerca con Google

193 Cerca con Google

clonal cells in myelodysplastic syndromes. Leukemia & lymphoma. 2007; 48 (7): Cerca con Google

1353–1371. Cerca con Google

Lichtenstein, A.V. Cancer: evolutionary, genetic and epigenetic aspects. Clin Epigenetics Cerca con Google

2010; 1, 85–100. Cerca con Google

Lin, X., Li, S., Zhao, Y., Ma, X., Zhang, K., He, X., and Wang, Z. Interaction domains of Cerca con Google

p62: a bridge between p62 and selective autophagy. DNA Cell Biol. 2013; 32, 220–227. Cerca con Google

Litchfield, D. W., Bosc, D. G., Canton, D. A., Saulnier, R. B., Vilk, G. and Zhang, C. Cerca con Google

Functional specialization of CK2 isoforms and characterization of isoform-specific Cerca con Google

binding partners. Molecular and cellular biochemistry, 2001; 227 (1-2), pp. 21–29. Cerca con Google

Litchfield, D. W., Bosc, D. G., Slominski, E. The protein kinase from mitotic human cells Cerca con Google

that phosphorylates Ser-209 on the casein kinase II beta-subunit is p34-cdc2. Cerca con Google

Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1995; 1269 (1), pp. Cerca con Google

69–78. Cerca con Google

Ljubimov A, Caballero S, Aoki A, Pinna L, Grant M, Castellon R. Involvement of protein Cerca con Google

kinase CK2 in angiogenesis and retinal neovascularization. Investigative ophthalmology Cerca con Google

& visual science. 2004; 45 (12): 4583-4591. Cerca con Google

Lolli G, Pinna L, Battistutta R. Structural determinants of protein kinase CK2 regulation by Cerca con Google

autoinhibitory polymerization. ACS Chemical Biology. 2012; 7 (7): 1158–1163. Cerca con Google

Lolli G, Ranchio A, Battistutta R. Active form of the Protein Kinase CK2 alpha-2 beta-2 Cerca con Google

holoenzyme is a strong complex with symmetric architecture. ACS chemical biology. Cerca con Google

2013. Cerca con Google

Lönn, U., and Lönn, S. 5,6-Dichloro-1-beta-O-ribofuranosylbenzimidazole induces DNA Cerca con Google

damage by interfering with DNA topoisomerase II. Eur. J. Biochem. 1987; 164, Cerca con Google

541–545. Cerca con Google

Lou, D. Y., Dominguez, I., Toselli, P., L, Esman-Bollag, E., O'brien, C. and Seldin, D. C. Cerca con Google

The alpha catalytic subunit of protein kinase CK2 is required for mouse embryonic Cerca con Google

Louvet, E., Junéra, H.R., Berthuy, I., and Hernandez-Verdun, D. Compartmentation of the Cerca con Google

nucleolar processing proteins in the granular component is a CK2-driven process. Mol. Cerca con Google

Biol. Cell 2006; 17, 2537–2546. Cerca con Google

Makowska M, Lukowska-Chojnacka E, Winska P, Kus A, Bilinska-Chomik A, Bretner M. Cerca con Google

Design and synthesis of CK2 inhibitors. Molecular and cellular biochemistry. 2011; Cerca con Google

356 (1-2): 91–96. Cerca con Google

Mann M, Ong S, Gronborg M, Steen H, Jensen O, P, Ey A. Analysis of protein Cerca con Google

phosphorylation using mass spectrometry: deciphering the phosphoproteome. Trends in Cerca con Google

biotechnology. 2002; 20 (6): 261–268. Cerca con Google

Manni, S., Brancalion, A., Tubi, L.Q., Colpo, A., Pavan, L., Cabrelle, A., Ave, E., Zaffino, Cerca con Google

F., Di Maira, G., Ruzzene, M., et al. Protein kinase CK2 protects multiple myeloma Cerca con Google

cells from ER stress-induced apoptosis and from the cytotoxic effect of HSP90 Cerca con Google

inhibition through regulation of the unfolded protein response. Clin. Cancer Res. 2012; Cerca con Google

18, 1888–1900. Cerca con Google

Manning B. Challenges and opportunities in defining the essential cancer kinome. Science Cerca con Google

signaling. 2009; 2 (63): 15. Cerca con Google

Manning G, Whyte D, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement Cerca con Google

of the human genome. Science. 2002; 298 (5600): 1912–1934. Cerca con Google

Marin, O., Meggio, F., Boldyreff, B., Issinger, O.G., and Pinna, L.A. Dissection of the dual Cerca con Google

function of the beta-subunit of protein kinase CK2 (casein kinase-2): a synthetic peptide Cerca con Google

reproducing the carboxyl-terminal domain mimicks the positive but not the negative Cerca con Google

effects of the whole protein. FEBS Lett. 1995; 363, 111–114. Cerca con Google

Marin O, Meggio F, Sarno S, Cesaro L, Pagano M, Pinna L. Tyrosine Versus Cerca con Google

Serine/Threonine Phosphorylation by Protein Kinase Casein Kinase-2 a study with Cerca con Google

peptide substrates derived from immunophilin Fpr3. Journal of Biological Chemistry. Cerca con Google

1999; 274 (41): 29260–29265. Cerca con Google

195 Cerca con Google

Marin, O., Sarno, S., Boschetti, M., Pagano, M.A., Meggio, F., Ciminale, V., D’Agostino, Cerca con Google

D.M., and Pinna, L.A. Unique features of HIV-1 Rev protein phosphorylation by Cerca con Google

protein kinase CK2 (casein kinase-2). FEBS Lett. 2000; 481, 63–67. Cerca con Google

Marusyk A, Polyak K. Tumor heterogeneity: causes and consequences. Biochimica et Cerca con Google

Biophysica Acta (BBA)-Reviews on Cancer. 2010; 1805 (1): 105–117. Cerca con Google

Matsumoto Y, Kunishio K, Nagao S. Increased phosphorylation of DNA topoisomerase II in Cerca con Google

etoposide resistant mutants of human glioma cell line. Journal of neuro-oncology. 1999; Cerca con Google

45 (1): 37–46. Cerca con Google

Mayo L, Seo Y, Jackson M, Smith M, Guzman J, Korgaonkar C, Donner D. Phosphorylation Cerca con Google

of human p53 at serine 46 determines promoter selection and whether apoptosis is Cerca con Google

attenuated or amplified. Journal of Biological Chemistry. 2005; 280 (28): 25953–25959. Cerca con Google

McDonnell MA, Abedin MJ, Melendez M, Platikanova TN, Ecklund JR, Ahmed K, Kelekar Cerca con Google

A. Phosphorylation of murine caspase-9 by the protein kinase casein kinase 2 regulates Cerca con Google

its cleavage by caspase-8. J Biol Chem. 2008; 283(29):20149-58. Cerca con Google

Meggio, F., Boldyreff, B., Issinger, O.G., and Pińna, L.A. Casein kinase 2 down-regulation Cerca con Google

and activation by polybasic peptides are mediated by acidic residues in the 55-64 region Cerca con Google

of the beta-subunit. A study with calmodulin as phosphorylatable substrate. Cerca con Google

Biochemistry 1994a 33, 4336–4342. Cerca con Google

Meggio, F., Boldyreff, B., Marin, O., Issinger, O. and Pinna, L. A. Phosphorylation and Cerca con Google

activation of protein kinase CK2 by p34cdc2 are independent events. European Journal Cerca con Google

of Biochemistry, 1995; 230 (3), pp. 1025–1031. Cerca con Google

Meggio F, Boldyreff B, Marin O, Marchiori F, Perich J, Issinger O, Pinna L. The effect of Cerca con Google

polylysine on casein-kinase-2 activity is influenced by both the structure of the Cerca con Google

protein/peptide substrates and the subunit composition of the enzyme. European Cerca con Google

Journal of Biochemistry. 1992; 205 (3): 939–945. Cerca con Google

Meggio, F., Marin, O., and Pinna, L.A. Substrate specificity of protein kinase CK2. Cell. Cerca con Google

Mol. Biol. Res. 1994b 40, 401–409. Cerca con Google

196 Cerca con Google

Meggio F, Pagano M, Moro S, Zagotto G, Ruzzene M, Sarno S, Cozza G, Bain J, Elliott M, Cerca con Google

Deana A, Others. Inhibition of protein kinase CK2 by condensed polyphenolic Cerca con Google

derivatives. An in vitro and in vivo study. Biochemistry. 2004; 43 (40): 12931–12936. Cerca con Google

Meggio F, Pinna L. One-thousand-and-one substrates of protein kinase CK2?. The FASEB Cerca con Google

Journal. 2003; 17 (3): 349–368. Cerca con Google

Michor, F., and Polyak, K. The origins and implications of intratumor heterogeneity. Cancer Cerca con Google

Prev Res (Phila) 2010; 3, 1361–1364 Cerca con Google

Miyata Y. Protein kinase CK2 in health and disease: CK2: the kinase controlling the Hsp90 Cerca con Google

chaperone machinery. Cell Mol Life Sci 2009; 66:1840–1849 Cerca con Google

Miyata Y., E. Nishida, CK2 controls multiple protein kinases by phosphorylating a Cerca con Google

kinase-targeting molecular chaperone Cdc37. Mol. Cell. Biol. 24 2004; 4065–4074 Cerca con Google

Miller, S.L.H., Malotky, E., and O’Bryan, J.P. Analysis of the role of ubiquitin-interacting Cerca con Google

motifs in ubiquitin binding and ubiquitylation. J. Biol. Chem. 2004; 279, 33528–33537. Cerca con Google

Mishra S., V. Pertz, B. Zhang, P. Kaur, H. Shimada, J. Groffen, Z. Kazimierczuk, L.A. Cerca con Google

Pinna, N. Heisterkamp, Treatment of P190 Bcr/Abl lymphoblastic leukemia cells with Cerca con Google

inhibitors of the serine/threonine kinase CK2, Leukemia 2007; 21 178–180. Cerca con Google

Monceviciūte-Eringiene, E. Neoplastic growth: the consequence of evolutionary malignant Cerca con Google

resistance to chronic damage for survival of cells (review of a new theory of the origin Cerca con Google

of cancer). Med. Hypotheses 2005; 65, 595–604. Cerca con Google

Musgrove E. A. and R. L. Sutherland, Biological determinants of endocrine resistance in Cerca con Google

breast cancer. Nature Reviews Cancer, 2009; vol. 9, no. 9, pp. 631–643 Cerca con Google

Nagar B, Bornmann W, Pellicena P, Schindler T, Veach D, Miller W, Clarkson B, Kuriyan J. Cerca con Google

Crystal structures of the kinase domain of c-Abl in complex with the small molecule Cerca con Google

inhibitors PD173955 and imatinib (STI-571). Cancer Research. 2002; 62 (15): Cerca con Google

4236–4243. Cerca con Google

Nahta R. and R. O’Regan. Evolving strategies for overcoming resistance to HER2-directed Cerca con Google

197 Cerca con Google

therapy: targeting the PI3K/Akt/mTOR pathway. Clinical Breast Cancer, 2010; vol. 10, Cerca con Google

supplement 3, pp. S72–S78 Cerca con Google

Newton A, C R. Protein kinase C: structural and spatial regulation by phosphorylation, Cerca con Google

cofactors, and macromolecular interactions. Chemical Reviews. 2001; 101 (8): Cerca con Google

2353–2364. Cerca con Google

Niefind K, Guerra B, Ermakowa I, Issinger O. Crystal structure of human protein kinase Cerca con Google

CK2: insights into basic properties of the CK2 holoenzyme. The EMBO journal. 2001; Cerca con Google

20 (19): 5320–5331. Cerca con Google

Niefind K, Guerra B, Pinna L, Issinger O, Schomburg D. Crystal structure of the catalytic Cerca con Google

subunit of protein kinase CK2 from Zea mays at 2.1 AA resolution. The EMBO journal. Cerca con Google

1998; 17 (9): 2451–2462. Cerca con Google

Nijman S. Synthetic lethality: general principles, utility and detection using genetic screens Cerca con Google

in human cells. FEBS letters. 2011; 585 (1): 1–6. Cerca con Google

Nobili S, L, Ini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs Cerca con Google

able to evade P-glycoprotein or to exploit its expression. Medicinal research reviews. Cerca con Google

2012; 32 (6): 1220–1262. Cerca con Google

O'brien, K. A., Lemke, S. J., Cocke, K. S., Rao, R. N. and Beckmann, R. P. Casein kinase 2 Cerca con Google

binds to and phosphorylates BRCA1. Biochemical and biophysical research Cerca con Google

communications, 1999; 260 (3), pp. 658–664. Cerca con Google

Oda Y, Sakamoto A, Satio T, Kawauchi S, Iwamoto Y, Tsuneyoshi M. Molecular Cerca con Google

abnormalities of p53, MDM2, and H-ras in synovial sarcoma. Modern Pathology. 2000; Cerca con Google

13 (9): 994–1004. Cerca con Google

Olsen B, Rasmussen T, Niefind K, Issinger O. Biochemical characterization of CK2 alpha Cerca con Google

and alpha-paralogues and their derived holoenzymes: evidence for the existence of a Cerca con Google

heterotrimeric CK2 alpha-holoenzyme forming trimeric complexes. Molecular and Cerca con Google

cellular biochemistry. 2008; 316 (1-2): 37–47. Cerca con Google

198 Cerca con Google

Pagano, M.A., Bain, J., Kazimierczuk, Z., Sarno, S., Ruzzene, M., Di Maira, G., Elliott, M., Cerca con Google

Orzeszko, A., Cozza, G., Meggio, F., et al. The selectivity of inhibitors of protein kinase Cerca con Google

CK2: an update. Biochem. J. 2008; 415, 353–365. Cerca con Google

Pagano M, Marin O, Cozza G, Sarno S, Meggio F, Treharne K, Mehta A, Pinna L. Cystic Cerca con Google

fibrosis transmembrane regulator fragments with the Phe508 deletion exert a dual Cerca con Google

allosteric control over the master kinase CK2. Biochem. J. 2010; 426: 19–29. Cerca con Google

Pagano M, Poletto G, Di Maira G, Cozza G, Ruzzene M, Sarno S, Bain J, Elliott M, Moro S, Cerca con Google

Zagotto G, Others. Tetrabromocinnamic acid (TBCA) and related compounds represent Cerca con Google

a new class of specific protein kinase CK2 inhibitors. Chembiochem. 2007; 8 (1): Cerca con Google

129–139. Cerca con Google

Pagano M, Sarno S, Poletto G, Cozza G, Pinna L, Meggio F. Autophosphorylation at the Cerca con Google

regulatory beta subunit reflects the supramolecular organization of protein kinase Cerca con Google

CK2. Molecular and cellular biochemistry. 2005; 274 (1-2): 23–29. Cerca con Google

Papinutto E, Ranchio A, Lolli G, Pinna L, Battistutta R. Structural and functional analysis of Cerca con Google

the flexible regions of the catalytic alpha-subunit of protein kinase CK2. Journal of Cerca con Google

Structural Biology. 2012; 177 (2): 382–391. Cerca con Google

Pargellis C, Tong L, Churchill L, Cirillo P, Gilmore T, Graham A, Grob P, Hickey E, Moss Cerca con Google

N, Pav S, Others. Inhibition of p38 MAP kinase by utilizing a novel allosteric binding Cerca con Google

site. Nature Structural & Molecular Biology. 2002; 9 (4): 268–272. Cerca con Google

Pierre F, Chua P, O’Brien S, Siddiqui-Jain A, Bourbon P, Haddach M, Michaux J, Nagasawa Cerca con Google

J, Schwaebe M, Stefan E, Others. Pre-clinical characterization of CX-4945, a potent and Cerca con Google

selective small molecule inhibitor of CK2 for the treatment of cancer. Molecular and Cerca con Google

cellular biochemistry. 2011; 356 (1-2): 37–43. Cerca con Google

Perea, S.E., Baladron, I., Garcia, Y., Perera, Y., Lopez, A., Soriano, J.L., Batista, N., Palau, Cerca con Google

A., Hernández, I., Farina, H., et al. CIGB-300, a synthetic peptide-based drug that Cerca con Google

targets the CK2 phosphoaceptor domain. Translational and clinical research. Mol. Cell. Cerca con Google

Biochem. 2011; 356, 45–50. Cerca con Google

199 Cerca con Google

Perea S, Reyes O, Baladron I, Perera Y, Farina H, Gil J, Rodriguez A, Bacardi D, Marcelo J, Cerca con Google

Cosme K, CIGB-300, a novel proapoptotic peptide that impairs the CK2 Cerca con Google

phosphorylation and exhibits anticancer properties both in vitro and in vivo. Molecular Cerca con Google

and cellular biochemistry. 2008; 316 (1-2): 163–167. Cerca con Google

Perea, S.E., Reyes, O., Puchades, Y., Mendoza, O., Vispo, N.S., Torrens, I., Santos, A., Cerca con Google

Silva, R., Acevedo, B., López, E., et al. Antitumor effect of a novel proapoptotic Cerca con Google

peptide that impairs the phosphorylation by the protein kinase 2 (casein kinase 2). Cerca con Google

Cancer Res. 2004; 64, 7127–7129. Cerca con Google

Perera, Y., Costales, H.C., Diaz, Y., Reyes, O., Farina, H.G., Mendez, L., Gómez, R.E., Cerca con Google

Acevedo, B.E., Gomez, D.E., Alonso, D.F., et al. Sensitivity of tumor cells towards Cerca con Google

CIGB-300 anticancer peptide relies on its nucleolar localization. J. Pept. Sci. 2012; 18, Cerca con Google

215–223. Cerca con Google

Perera, Y., Farina, H.G., Gil, J., Rodriguez, A., Benavent, F., Castellanos, L., Gómez, R.E., Cerca con Google

Acevedo, B.E., Alonso, D.F., and Perea, S.E. Anticancer peptide CIGB-300 binds to Cerca con Google

nucleophosmin/B23, impairs its CK2-mediated phosphorylation, and leads to apoptosis Cerca con Google

through its nucleolar disassembly activity. Mol. Cancer Ther. 2009; 8, 1189–1196. Cerca con Google

Perera, Y., Farina, H.G., Hernández, I., Mendoza, O., Serrano, J.M., Reyes, O., Gómez, D.E., Cerca con Google

Gómez, R.E., Acevedo, B.E., Alonso, D.F., et al. Systemic administration of a peptide Cerca con Google

that impairs the protein kinase (CK2) phosphorylation reduces solid tumor growth in Cerca con Google

mice. Int. J. Cancer 2008; 122, 57–62. Cerca con Google

Perez D, Gil C, Martinez A. Protein kinases CK1 and CK2 as new targets for Cerca con Google

neurodegenerative diseases. Medicinal research reviews. 2011; 31 (6): 924–954. Cerca con Google

Perez E. A. Impact, mechanisms, and novel chemotherapy strategies for overcoming Cerca con Google

resistance to anthracyclines and taxanes inmetastatic breast cancer, Breast Cancer Cerca con Google

Research and Treatment, 2009; vol. 114, no. 2, pp. 195–201, Cerca con Google

Piazza F, Ruzzene M, Gurrieri C, Montini B, Bonanni L, Chioetto G, Di Maira G, Barbon F, Cerca con Google

Cabrelle A, Zambello R, Others. Multiple myeloma cell survival relies on high activity Cerca con Google

200 Cerca con Google

of protein kinase CK2. Blood. 2006; 108 (5): 1698–1707. Cerca con Google

Pierantoni G, Bulfone A, Pentimalli F, Fedele M, Iuliano R, Santoro M, Chiariotti L, Cerca con Google

Ballabio A, Fusco A. The homeodomain-interacting protein kinase 2 gene is expressed Cerca con Google

late in embryogenesis and preferentially in retina, muscle, and neural tissues. Cerca con Google

Biochemical and biophysical research communications. 2002; 290 (3): 942–947. Cerca con Google

Pinna L. Protein kinase CK2. Ames, Iowa, USA: Wiley-Blackwell; 2013. Cerca con Google

Pinna L. Protein kinase CK2: a challenge to canons. Journal of cell science. 2002; 115 (20): Cerca con Google

3873–3878. Cerca con Google

Pinna, L.A., and Ruzzene, M. How do protein kinases recognize their substrates? Biochim. Cerca con Google

Biophys. Acta 1996; 1314, 191–225. Cerca con Google

Prelle, A., Sciacco, M., Tancredi, L., Fagiolari, G., Comi, G.P., Ciscato, P., Serafini, M., Cerca con Google

Fortunato, F., Zecca, C., Gallanti, A., et al. Clinical, morphological and immunological Cerca con Google

evaluation of six patients with dysferlin deficiency. Acta Neuropathol. 2003; 105, Cerca con Google

537–542. Cerca con Google

Prins, R.C., Burke, R.T., Tyner, J.W., Druker, B.J., Loriaux, M.M., and Spurgeon, S.E. Cerca con Google

CX-4945, a selective inhibitor of casein kinase-2 (CK2), exhibits anti-tumor activity in Cerca con Google

hematologic malignancies including enhanced activity in chronic lymphocytic leukemia Cerca con Google

when combined with fludarabine and inhibitors of the B-cell receptor pathway. Cerca con Google

Leukemia 2013; 27, 2094–2096. Cerca con Google

Prudent R, Moucadel V, Laudet B, Barette C, Lafanech`Ere L, Hasenknopf B, Li J, Bareyt S, Cerca con Google

Lac^Ote E, Thorimbert S, Others. Identification of polyoxometalates as nanomolar Cerca con Google

noncompetitive inhibitors of protein kinase CK2. Chemistry & biology. 2008; 15 (7): Cerca con Google

683–692. Cerca con Google

Prudent, R., Moucadel, V., Nguyen, C.-H., Barette, C., Schmidt, F., Florent, J.-C., Cerca con Google

Lafanechère, L., Sautel, C.F., Duchemin-Pelletier, E., Spreux, E., et al. Antitumor Cerca con Google

activity of pyridocarbazole and benzopyridoindole derivatives that inhibit protein kinase Cerca con Google

CK2. Cancer Res. 2010; 70, 9865 Cerca con Google

homeodomain-interacting protein kinase-2 knockdown. Cancer research. 2008; 68 (10): Cerca con Google

3707–3714. Cerca con Google

Puca R, Nardinocchi L, Givol D, D'orazi G. Regulation of p53 activity by HIPK2: molecular Cerca con Google

mechanisms and therapeutical implications in human cancer cells. Oncogene. 2010; 29 Cerca con Google

(31): 4378–4387. Cerca con Google

Pusztai L., P. Wagner, N. Ibrahim et al., Phase II study of tariquidar, a selective Cerca con Google

P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast Cerca con Google

carcinoma. Cancer, 2005; vol. 104, no. 4, pp. 682–691 Cerca con Google

Quotti Tubi, L., Gurrieri, C., Brancalion, A., Bonaldi, L., Bertorelle, R., Manni, S., Pavan, L., Cerca con Google

Lessi, F., Zambello, R., Trentin, L., et al. Inhibition of protein kinase CK2 with the Cerca con Google

clinical-grade small ATP-competitive compound CX-4945 or by RNA interference Cerca con Google

unveils its role in acute myeloid leukemia cell survival, p53-dependent apoptosis and Cerca con Google

daunorubicin-induced cytotoxicity. J Hematol Oncol 2013; 6, 78. Cerca con Google

Quintaje S, Orchard S, Ra. The Annotation of Both Human and Mouse Kinomes in Cerca con Google

UniProtKB/Swiss-Prot One Small Step in Manual Annotation, One Giant Leap for Full Cerca con Google

Comprehension of Genomes. Molecular & Cellular Proteomics. 2008; 7 (8): Cerca con Google

1409–1419. Cerca con Google

Raaf J, Brunstein E, Issinger O, Niefind K. The interaction of CK2-alpha and CK2-beta, the Cerca con Google

subunits of protein kinase CK2, requires CK2-beta in a preformed conformation and is Cerca con Google

enthalpically driven. Protein Science. 2008; 17 (12): 2180–2186. Cerca con Google

Richard, J.P., Melikov, K., Brooks, H., Prevot, P., Lebleu, B., and Chernomordik, L.V. Cerca con Google

Cellular uptake of unconjugated TAT peptide involves clathrin-dependent endocytosis Cerca con Google

and heparan sulfate receptors. J. Biol. Chem. 2005; 280, 15300–15306. Cerca con Google

Rinaldo C, Prodosmo A, Siepi F, Soddu S. HIPK2: a multitalented partner for transcription Cerca con Google

factors in DNA damage response and development This paper is one of a selection of Cerca con Google

202 Cerca con Google

papers published in this Special Issue, entitled 28th International West Coast Chromatin Cerca con Google

and Chromosome Conference, and has undergone the Journal's usual peer review Cerca con Google

process. Biochemistry and Cell Biology. 2007; 85 (4): 411–418. Cerca con Google

Rivers A, Gietzen K, Vielhaber E, Virshup D. Regulation of casein kinase I epsilon and Cerca con Google

casein kinase I delta by an in vivo futile phosphorylation cycle. Journal of Biological Cerca con Google

Chemistry. 1998; 273 (26): 15980–15984. Cerca con Google

Rodríguez-Ulloa, A., Ramos, Y., Gil, J., Perera, Y., Castellanos-Serra, L., García, Y., Cerca con Google

Betancourt, L., Besada, V., González, L.J., Fernández-de-Cossio, J., et al. Proteomic Cerca con Google

profile regulated by the anticancer peptide CIGB-300 in non-small cell lung cancer Cerca con Google

(NSCLC) cells. J. Proteome Res. 2010; 9, 5473–5483. Cerca con Google

Roscic A, Moller A, Calzado M, Renner F, Wimmer V, Gresko E, Ludi K, Schmitz M. Cerca con Google

Phosphorylation-dependent control of Pc2 SUMO E3 ligase activity by its substrate Cerca con Google

protein HIPK2. Molecular cell. 2006; 24 (1): 77–89. Cerca con Google

Ruzzene M, Penzo D, Pinna L. Protein kinase CK2 inhibitor 4, 5, 6, Cerca con Google

7-tetrabromobenzotriazole (TBB) induces apoptosis and caspase-dependent degradation Cerca con Google

of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. Biochem. J. Cerca con Google

2002; 364: 41–47. Cerca con Google

Ruzzene M, Pinna L. Addiction to protein kinase CK2: a common denominator of diverse Cerca con Google

cancer cells? Biochimica et Biophysica Acta (BBA)-Proteins and Proteomics. 2010; Cerca con Google

1804 (3): 499–504. Cerca con Google

Salvi M, Cesaro L, Tibaldi E, Pinna L. Motif analysis of phosphosites discloses a potential Cerca con Google

prominent role of the Golgi casein kinase (GCK) in the generation of human plasma Cerca con Google

phospho-proteome. Journal of proteome research. 2010; 9 (6): 3335–3338. Cerca con Google

Salvi M, Sarno S, Cesaro L, Nakamura H, Pinna L. Extraordinary pleiotropy of protein Cerca con Google

kinase CK2 revealed by weblogo phosphoproteome analysis. Biochimica et Biophysica Cerca con Google

Acta (BBA)-Molecular Cell Research. 2009; 1793 (5): 847–859. Cerca con Google

Salvi, M., Sarno, S., Marin, O., Meggio, F., Itarte, E., and Pinna, L.A. Discrimination Cerca con Google

203 Cerca con Google

between the activity of protein kinase CK2 holoenzyme and its catalytic subunits. FEBS Cerca con Google

Lett. 2006; 580, 3948–3952. Cerca con Google

Sandholt, I.S., Olsen, B.B., Guerra, B., and Issinger, O.-G. Resorufin: a lead for a new Cerca con Google

protein kinase CK2 inhibitor. Anticancer Drugs 2009; 20, 238–248. Cerca con Google

Sarno S, Demoliner E, Ruzzene M, Pagano M, Battistutta R, Bain J, Fabbro D, Schoepfer J, Cerca con Google

Elliott M, Furet P, Others. Biochemical and three-dimensional-structural study of the Cerca con Google

specific inhibition of protein kinase CK2 by [5-oxo-5, 6-dihydroindolo-(1, 2-a) Cerca con Google

quinazolin-7-yl] acetic acid (IQA). Biochem. J. 2003; 374: 639–646. Cerca con Google

Sarno S, Moro S, Meggio F, Zagotto G, Dal Ben D, Ghisellini P, Battistutta R, Zanotti G, Cerca con Google

Pinna L. Toward the rational design of protein kinase casein kinase-2 inhibitors. Cerca con Google

Pharmacology & therapeutics. 2002; 93 (2): 159–168. Cerca con Google

Sarno S, Reddy H, Meggio F, Ruzzene M, Davies S, Donella-Deana A, Shugar D, Pinna L. Cerca con Google

Selectivity of 4, 5, 6, 7-tetrabromobenzotriazole, an ATP site-directed inhibitor of Cerca con Google

protein kinase CK2 (casein kinase-2). FEBS letters. 2001; 496 (1): 44–48. Cerca con Google

Sarno S, Ruzzene M, Frascella P, Pagano M, Meggio F, Zambon A, Mazzorana M, Di Maira Cerca con Google

G, Lucchini V, Pinna L. Development and exploitation of CK2 inhibitors. Molecular Cerca con Google

and cellular biochemistry. 2005; 274 (1-2): 69–76. Cerca con Google

Sarno, S., Vaglio, P., Marin, O., Meggio, F., Issinger, O. and Pinna, L. A. Basic Residues in Cerca con Google

the 74–83 and 191–198 Segments of Protein Kinase CK2 Catalytic Subunit are Cerca con Google

Implicated in Negative but not in Positive Regulation by the beta-Subunit. European Cerca con Google

Journal of Biochemistry, 1997; 248 (2), pp. 290–295. Cerca con Google

Sass, G., Klinger, N., Sirma, H., Hashemolhosseini, S., Hellerbrand, C., Neureiter, D., Wege, Cerca con Google

H., Ocker, M., and Tiegs, G. Inhibition of experimental HCC growth in mice by use of Cerca con Google

the kinase inhibitor DMAT. Int. J. Oncol. 2011; 39, 433–442. Cerca con Google

Seeram N, Henning S, Zhang Y, Suchard M, Li Z, Heber D. Pomegranate juice ellagitannin Cerca con Google

metabolites are present in human plasma and some persist in urine for up to 48 hours. Cerca con Google

The Journal of nutrition. 2006; 136 (10): 2481–2485. Cerca con Google

204 Cerca con Google

Seger D, Seger R, Shaltiel D. The CK2 phosphorylation of vitronectin: Promotion of cell Cerca con Google

adhesion via the 3-phosphatidylinositol 3-kinase pathway. J Biol Chem. 2001; Cerca con Google

276:16998–17006 Cerca con Google

Seldin D.C., P. Leder, Casein kinase II alpha transgene-induced murine lymphoma: relation Cerca con Google

to theileriosis in cattle, Science 1995; 267 894–897 Cerca con Google

Shin, J. P62 and the sequestosome, a novel mechanism for protein metabolism. Arch. Pharm. Cerca con Google

Res. 1998; 21, 629–633. Cerca con Google

Siddiqui-Jain, A., Bliesath, J., Macalino, D., Omori, M., Huser, N., Streiner, N., Ho, C.B., Cerca con Google

Anderes, K., Proffitt, C., O’Brien, S.E., et al. CK2 inhibitor CX-4945 suppresses DNA Cerca con Google

repair response triggered by DNA-targeted anticancer drugs and augments efficacy: Cerca con Google

mechanistic rationale for drug combination therapy. Mol. Cancer Ther. 2012; 11, Cerca con Google

994–1005. Cerca con Google

Silva A., J.A. Yunes, B.A. Cardoso, L.R. Martins, P.Y. Jotta, M. Abecasis, A.E. Nowill, N.R. Cerca con Google

Leslie, A.A. Cardoso, J.T. Barata, PTEN posttranslational inactivation and Cerca con Google

hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability, J. Cerca con Google

Clin. Invest. 2008; 118 3762–3774 Cerca con Google

Soderling T. Protein kinases. Regulation by autoinhibitory domains. J Biol Chem. 1990; 265 Cerca con Google

(4): 1823–1826. Cerca con Google

Solares, A.M., Santana, A., Baladrón, I., Valenzuela, C., González, C.A., Díaz, A., Castillo, Cerca con Google

D., Ramos, T., Gómez, R., Alonso, D.F., et al. Safety and preliminary efficacy data of a Cerca con Google

novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose Cerca con Google

levels in patients with cervical malignancies. BMC Cancer 2009; 9, 146. Cerca con Google

Solimini NL, Luo J, Elledge SJ Non-oncogene addiction and the stress phenotype of cancer Cerca con Google

cells. Cell 2007; 130:986–988 Cerca con Google

Stauber, R.H., and Pavlakis, G.N. Intracellular trafficking and interactions of the HIV-1 Tat Cerca con Google

protein. Virology 1998; 252, 126–136. Cerca con Google

205 Cerca con Google

Stepanova V, et al. Urokinase-dependent human vascular smooth muscle cell adhesion Cerca con Google

requires selective vitronectin phosphorylation by ectoprotein kinase CK2. J Biol Chem Cerca con Google

2002; 277:10265–10272. Cerca con Google

Stolarczyk E, Reiling C, Pickin K, Coppage R, Knecht M, Paumi C. Casein kinase 2-alpha Cerca con Google

regulates multidrug resistance-associated protein 1 function via phosphorylation of Cerca con Google

Thr249. Molecular Pharmacology. 2012; 82 (3): 488–499. Cerca con Google

Suzuki Y, Cluzeau J, Hara T, Hirasawa A, Tsujimoto G, Oishi S, Ohno H, Fujii N. Cerca con Google

Structure-Activity Relationships of Pyrazine-Based CK2 Inhibitors: Synthesis and Cerca con Google

Evaluation of 2, 6-Disubstituted Pyrazines and 4, 6-Disubstituted Pyrimidines. Archiv Cerca con Google

der Pharmazie. 2008; 341 (9): 554–561. Cerca con Google

Szebeni, A., Hingorani, K., Negi, S., and Olson, M.O.J. Role of protein kinase CK2 Cerca con Google

phosphorylation in the molecular chaperone activity of nucleolar protein b23. J. Biol. Cerca con Google

Chem. 2003 278, 9107–9115. Cerca con Google

Taylor S, Kornev A, P R. Protein kinases: evolution of dynamic regulatory proteins. Trends Cerca con Google

in biochemical sciences. 2011; 36 (2): 65–77. Cerca con Google

Taylor S, Radzio-Andzelm E, Knighton D, Ten Eyck L, Sowadski J, Herberg F, Yonemoto Cerca con Google

W, Zheng J. Crystal structures of the catalytic subunit of cAMP-dependent protein Cerca con Google

kinase reveal general features of the protein kinase family. Receptor. 1993; 3 (3): 165. Cerca con Google

Tan, Y.-J., Teng, E., and Ting, A.E. A small inhibitor of the interaction between Bax and Cerca con Google

Bcl-X(L) can synergize with methylprednisolone to induce apoptosis in Cerca con Google

Bcl-X(L)-overexpressing breast-cancer cells. J. Cancer Res. Clin. Oncol. 2003 129, Cerca con Google

437–448. Cerca con Google

Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K. Protein kinase CK2 signal in Cerca con Google

neoplasia. Histol Histopathol 2001; 16:573–582 Cerca con Google

Tchernev, V. T., Mansfield, T. A., Giot, L., Kumar, A. M., N, Abalan, K., Li, Y., Mishra, V. Cerca con Google

S., Detter, J. C., Rothberg, J. M., Wallace, M. R. and Others. The Chediak-Higashi Cerca con Google

protein interacts with SNARE complex and signal transduction proteins. Molecular Cerca con Google

206 Cerca con Google

Medicine, 2002; 8 (1), p. 56. Cerca con Google

Thornberry, N. A., Rano, T. A., Peterson, E. P., Rasper, D. M., Timkey, T., Garcia-Calvo, Cerca con Google

M., Houtzager, V. M., Nordstrom, P. A., Roy, S., Vaillancourt, J. P. et al. A Cerca con Google

combinatorial approach of members of the caspase family and granzyme B. Functional Cerca con Google

relationships established for key mediators of apoptosis. J. Biol. Chem. 1997; 272, Cerca con Google

17907– 17911 Cerca con Google

Torres J, Rodriguez J, Myers MP, Valiente M, Graves JD, Tonks NK, Pulido R Cerca con Google

Phosphorylation-regulated cleavage of the tumor suppressor PTEN by caspase-3: Cerca con Google

implications for the control of protein stability and PTEN-protein interactions. J Biol Cerca con Google

Chem. 2003; 278(33):30652-60. Cerca con Google

Trock B, Leonessa F, Clarke R. Multidrug resistance in breast cancer: a meta-analysis of Cerca con Google

MDR1/gp170 expression and its possible functional significance. Journal of the Cerca con Google

National Cancer Institute. 1997; 89 (13): 917–931. Cerca con Google

Truant, R., and Cullen, B.R. The arginine-rich domains present in human immunodeficiency Cerca con Google

virus type 1 Tat and Rev function as direct importin beta-dependent nuclear localization Cerca con Google

signals. Mol. Cell. Biol. 1999; 19, 1210–1217. Cerca con Google

Tucker C, Fields S. Lethal combinations. Nature genetics. 2003; 35 (3): 204–205. Cerca con Google

Unger G.M., A.T. Davis, J.W. Slaton, K. Ahmed, Protein kinase CK2 as regulator of cell Cerca con Google

survival: implications for cancer therapy, Curr. Cancer Drug Targets 2004; 4 77–84. Cerca con Google

Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and Cerca con Google

future perspectives in HER2-overexpressing breast cancer. Annals of oncology. 2007; Cerca con Google

18 (6): 977–984. Cerca con Google

Valero E, De Bonis S, Filhol O, Wade R, Langowski J, Chambaz E, Cochet C. Quaternary Cerca con Google

Structure of Casein Kinase 2 characterization of multiple oligomeric states and relation Cerca con Google

with its catalytic activity. Journal of Biological Chemistry. 1995; 270 (14): Cerca con Google

8345–8352. Cerca con Google

207 Cerca con Google

Vener, O A, Pagano M, Tosoni K, Meggio F, Cassidy D, Stobbart M, Pinna L, Mehta A. Cerca con Google

Understanding protein kinase CK2 mis-regulation upon F508del CFTR expression. Cerca con Google

Naunyn-Schmiedeberg's archives of pharmacology. 2011; 384 (4-5): 473—488 Cerca con Google

Venerando, A., Pagano, M.A., Tosoni, K., Meggio, F., Cassidy, D., Stobbart, M., Pinna, Cerca con Google

L.A., and Mehta, A. Understanding protein kinase CK2 mis-regulation upon F508del Cerca con Google

CFTR expression. Naunyn Schmiedebergs Arch. Pharmacol. 2011; 384, 473–488. Cerca con Google

Vilk G, Saulnier R, Pierre R, Litchfield D. Inducible expression of protein kinase CK2 in Cerca con Google

mammalian cells. Evidence for functional specialization of CK2 isoforms. Journal of Cerca con Google

Biological Chemistry. 1999; 274 (20): 14406–14414. Cerca con Google

Wadia, J.S., and Dowdy, S.F. Transmembrane delivery of protein and peptide drugs by Cerca con Google

TAT-mediated transduction in the treatment of cancer. Adv. Drug Deliv. Rev. 2005; 57, Cerca con Google

579–596. Cerca con Google

Wallace M, Adams M, Kanouni T, Mol C, Dougan D, Feher V, O’Connell S, Shi L, Cerca con Google

Halkowycz P, Dong Q. Structure-based design and synthesis of pyrrole derivatives as Cerca con Google

MEK inhibitors. Bioorganic & medicinal chemistry letters. 2010; 20 (14): 4156–4158. Cerca con Google

Widder J, Chen W, Li L, Dikalov S, Th"Ony B, Hatakeyama K, Harrison D. Regulation of Cerca con Google

tetrahydrobiopterin biosynthesis by shear stress. Circulation research. 2007; 101 (8): Cerca con Google

830–838. Cerca con Google

Wirkner, U., Voss, H., Lichter, P. and Pyerin, W. Human protein kinase CK2 genes. Cellular Cerca con Google

& molecular biology research, 1994; 40 (5-6), p. 489. Cerca con Google

Yamada D, P'Erez-Torrado R, Filion G, Caly M, Jammart B, Devignot V, Sasai N, Ravassard Cerca con Google

P, Mallet J, Sastre-Garau X, Others. The human protein kinase HIPK2 phosphorylates Cerca con Google

and downregulates the methyl-binding transcription factor ZBTB4. Oncogene. 2009; 28 Cerca con Google

(27): 2535–2544. Cerca con Google

Yamane, K. and Kinsella, T. J. CK2 inhibits apoptosis and changes its cellular localization Yang-Feng, T. L., Naiman, T., Kopatz, I., Eli, D., Dafni, N. and Canaani, D. Assignment of Cerca con Google

the human casein kinase II [alpha][prime] subunit gene (CSNK2A1) to chromosome Cerca con Google

16p13. 2-p13. 3. Genomics;(United States), 1994; 19 (1). Cerca con Google

Yao K, Youn H, Gao X, Huang B, Zhou F, Li B, Han H. Casein kinase 2 inhibition Cerca con Google

attenuates androgen receptor function and cell proliferation in prostate cancer cells. The Cerca con Google

Prostate. 2012; 72 (13): 1423–1430. Cerca con Google

Yin, X., Gu, S. and Jiang, J. X. Regulation of lens connexin 45.6 by apoptotic protease, Cerca con Google

caspase-3. Cell Adhesion Commun. 2001; 8, 373– 376 Cerca con Google

Xu, X., Toselli, P. A., Russell, L. D. and Seldin, D. C. Globozoospermia in mice lacking the Cerca con Google

casein kinase II alpha catalytic subunit. Nat. Genet. 1999; 23, 118– 121 Cerca con Google

Zahreddine H, Borden K. Mechanisms and insights into drug resistance in cancer. Frontiers Cerca con Google

in pharmacology. 2013; 4. Cerca con Google

Zanin, S., Borgo, C., Girardi, C., O’Brien, S.E., Miyata, Y., Pinna, L.A., Donella-Deana, A., Cerca con Google

and Ruzzene, M. Effects of the CK2 inhibitors CX-4945 and CX-5011 on drug-resistant Cerca con Google

cells. PLoS ONE, 2012; 7, e49193. Cerca con Google

Zhang, C., Vilk, G., Canton, D. A. and Litchfield, D. W. Phosphorylation regulates the Cerca con Google

stability of the regulatory CK2beta subunit. Oncogene, 2002; 21 (23), pp. 3754–3764. Cerca con Google

Zheng, Y., McFarland, B.C., Drygin, D., Yu, H., Bellis, S.L., Kim, H., Bredel, M., and Cerca con Google

Benveniste, E.N. Targeting protein kinase CK2 suppresses prosurvival signaling Cerca con Google

pathways and growth of glioblastoma. Clin. Cancer Res. 2013; 19, 6484–6494. Cerca con Google

Ziegler, A., and Seelig, J. Interaction of the protein transduction domain of HIV-1 TAT with Cerca con Google

heparan sulfate: binding mechanism and thermodynamic parameters. Biophys. J. 2004; Cerca con Google

86, 254–263. Cerca con Google

Zimina EP, et al. Extracellular phosphorylation of collagen XVII by ecto-CK2 inhibits Cerca con Google

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