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Masiero, Massimo (2009) Induzione della fosfatasi MKP-1 ad opera di NOTCH3: ruolo di questa proteina nell'apoptosi in cellule di leucemia T. [Tesi di dottorato]

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Abstract (inglese)

T cell acute lymphoblastic leukaemia (T-ALL) is a thymocyte's derived malignant disease characterized by an abnormal lymphoblast numbers that represents 10-15% of all leukaemias in childhood and 25% in adulthood. The Notch pathway has been involved in the pathogenesis of this disease. This is an evolutionary conserved pathway involved not only in leukaemia biology but also in different physiologic processes, including T cell differentiation and angiogenesis. New blood vessels development is mandatory to foster tumor growth, because insufficient perfusion can induce the establishment of a state of dormancy, a condition characterized by sustained tumor latency.
The present thesis work tries to expand our knowledge on the mechanisms involved in regulation of tumor dormancy by exploiting a T-ALL model where escape from dormancy is due to activation of Notch3 signalling induced by angiogenesis. We investigated the mechanisms downstream to this activation. Moreover, we tried to extend our findings to other T-ALL cells in order to draw some therapeutic implications.
This study demonstrated that escape from tumor dormancy is connected with low activation of MAPKs ERK1/2 and p38, in part confirming literature data describing the involvement of this signalling pathway in dormancy. In parallel to MAPKs silencing we found an increase in MKP-1 expression, a phosphatase known to target ERK1/2 and p38 by inhibiting their activity. We demonstrated that MKP-1 upregulation is induced by Notch3 activation through a mechanism based on reduction of its ubiquitination and protein degradation.
We further investigated the role of MKP-1 in our model, demonstrating that its overexpression is not sufficient to prevent tumor dormancy, but yet MKP-1 expression is important in early phases of tumor growth. This role seems to be linked to MKP-1 anti-apoptotic properties following challenge of T-ALL cells with serum starvation and some chemotherapeutic drugs.
In conclusion, our findings describe on MKP-1 phosphatase as one key effector of the anti-apoptotic activities of Notch3 that, in our model, regulates escape from dormancy. We also demonstrated that Notch3 control of MKP-1 levels is mediated by protein stabilization, an uncommon mechanism for this class of receptors usually involved in gene expression regulation.
Finally, we confirmed the strong anti-apoptotic properties of MKP-1 in T-ALL cells, a finding which could have therapeutic implications.

Abstract (italiano)

La leucemia linfoblastica acuta a cellule T (T-ALL) è un'emopatia maligna dei timociti caratterizzata da un alto numero di linfoblasti che rappresenta il 10-15% dei casi di leucemia in età pediatrica ed il 25% dei casi in età adulta. Tra le vie di signalling maggiormente coinvolte in questo tipo di neoplasia figura quello governato dai recettori Notch. Questa pathway evolutivamente conservata, oltre ad essere alterata in queste leucemie, ricopre un ruolo molto importante anche in diversi processi fisiologici, tra cui ricordiamo il differenziamento dei linfociti T e l'angiogenesi. Lo sviluppo di nuovi vasi sanguigni è un evento centrale nello sviluppo tumorale in quanto un'insufficiente perfusione può determinare, tra l'altro, l'instaurarsi di uno stato di dormienza, una condizione caratterizzata dalla stasi prolungata della crescita tumorale.
Il presente lavoro propone di ampliare le conoscenze sul fenomeno della dormienza tumorale impiegando un modello in cui cellule di T-ALL sono in grado di sfuggire dallo stato di dormienza grazie all'attivazione del signalling di Notch3, e di indagare più in dettaglio quelli che sono i meccanismi a valle di questa attivazione. Inoltre, si è cercato di estendere le evidenze ottenute in questo modello anche ad altre cellule di T-ALL traendone anche alcune implicazioni terapeutiche.
Lo studio ha dimostrato che la condizione di uscita dalla dormienza è associata ad una diminuzione dell'attivazione delle MAP chinasi ERK1/2 e p38, confermando in parte dati di letteratura che descrivono il coinvolgimento di queste vie di signalling nel fenomeno della dormienza tumorale. Parallelamente a questo spegnimento delle MAP chinasi è stato rilevato un aumento dei livelli della fosfatasi MKP-1. Abbiamo quindi dimostrato che l'incremento di questa ultima è indotto dall'attivazione di Notch3, attraverso un meccanismo basato sulla riduzione dell'ubiquitinazione di MKP-1 e quindi sulla conseguente stabilizzazione della proteina.
E' stato successivamente indagato il ruolo di questa fosfatasi nel nostro modello, dimostrando che la sua overespressione da sola non è sufficiente a interrompere lo stato di dormienza, ma che, nonostante questo, risulta essere comunque importante nelle prime fasi di crescita tumorale. Questo suo ruolo sembra essere legato alla capacità di MKP-1 di proteggere le cellule di T-ALL dall'apoptosi, sia in condizioni di stress cellulare che a seguito di trattamento con alcuni chemioterapici.
In conclusione, le nostre ricerche hanno individuato nella fosfatasi MKP-1 uno degli effettori dell'attività anti-apoptotica e di Notch3 che, nel nostro modello, sembra essere coinvolta nell'uscita dalla condizione di dormienza tumorale. Abbiamo inoltre dimostrato che l'azione di Notch3 è mediata da un meccanismo atipico per questa classe di recettori, molto più comunemente coinvolti nella regolazione della trascrizione genica. In ultimo, abbiamo dimostrato le rilevanti capacità anti-apoptotiche di MKP-1, formulando quindi l'ipotesi che l'espressione di questa proteina possa avere anche un significato traslazionale per la terapia delle T-ALL.

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Tipo di EPrint:Tesi di dottorato
Relatore:Indraccolo, Stefano
Dottorato (corsi e scuole):Ciclo 21 > Corsi per il 21simo ciclo > ONCOLOGIA E ONCOLOGIA CHIRURGICA
Data di deposito della tesi:29 Gennaio 2009
Anno di Pubblicazione:2009
Parole chiave (italiano / inglese):Notch, MKP-1, dormienza tumorale, T-ALL
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/06 Oncologia medica
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Oncologiche e Chirurgiche
Codice ID:1719
Depositato il:29 Gen 2009
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