Mcl-1 is a unique Bcl-2 family member that plays crucial roles in apoptosis. Apoptosis-unrelated functions of Mcl-1 are however emerging, further justifying its tight regulation. Here we unravel a novel mechanism of Mcl-1 regulation mediated by the haplo-insufficient tumour suppressor Beclin 1. Beclin 1 negatively modulates Mcl-1 stability in a reciprocal manner whereby depletion of one leads to the stabilization of the other. This co-regulation is independent of autophagy and of their physical interaction. Both Beclin 1 and Mcl-1 are deubiquitinated and thus stabilized by binding to a common deubiquitinase, USP9X. Beclin 1 and Mcl-1 negatively modulate the proteasomal degradation of each other through competitive displacement of USP9X. The analysis of patient-derived melanoma cells and tissue samples shows that the levels of Beclin 1 decrease, while Mcl-1 levels subsequently increase during melanoma progression in a significant inter-dependent manner. The identified inverse co-regulation of Beclin 1 and Mcl-1 represents a mechanism of functional counteraction in cancer.

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner / M. Elgendy, M. Ciro, A.K. Abdel Aziz, G. Belmonte, R. Dal Zuffo, C. Mercurio, C. Miracco, L. Lanfrancone, M. Foiani, S. Minucci. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 5:(2014), pp. 5637.1-5637.11. [10.1038/ncomms6637]

Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner

R. Dal Zuffo;M. Foiani
Penultimo
;
S. Minucci
2014

Abstract

Mcl-1 is a unique Bcl-2 family member that plays crucial roles in apoptosis. Apoptosis-unrelated functions of Mcl-1 are however emerging, further justifying its tight regulation. Here we unravel a novel mechanism of Mcl-1 regulation mediated by the haplo-insufficient tumour suppressor Beclin 1. Beclin 1 negatively modulates Mcl-1 stability in a reciprocal manner whereby depletion of one leads to the stabilization of the other. This co-regulation is independent of autophagy and of their physical interaction. Both Beclin 1 and Mcl-1 are deubiquitinated and thus stabilized by binding to a common deubiquitinase, USP9X. Beclin 1 and Mcl-1 negatively modulate the proteasomal degradation of each other through competitive displacement of USP9X. The analysis of patient-derived melanoma cells and tissue samples shows that the levels of Beclin 1 decrease, while Mcl-1 levels subsequently increase during melanoma progression in a significant inter-dependent manner. The identified inverse co-regulation of Beclin 1 and Mcl-1 represents a mechanism of functional counteraction in cancer.
No
English
targeting MCL-1; prostate-cancer; melanoma-cells; apoptosis; expression; resistance; survival; therapy; inhibition; sabutoclax
Settore BIO/11 - Biologia Molecolare
Articolo
Esperti anonimi
Pubblicazione scientifica
2014
Nature Publishing Group
5
5637
1
11
11
Pubblicato
Periodico con rilevanza internazionale
pubmed
Aderisco
info:eu-repo/semantics/article
Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner / M. Elgendy, M. Ciro, A.K. Abdel Aziz, G. Belmonte, R. Dal Zuffo, C. Mercurio, C. Miracco, L. Lanfrancone, M. Foiani, S. Minucci. - In: NATURE COMMUNICATIONS. - ISSN 2041-1723. - 5:(2014), pp. 5637.1-5637.11. [10.1038/ncomms6637]
open
Prodotti della ricerca::01 - Articolo su periodico
10
262
Article (author)
Periodico con Impact Factor
M. Elgendy, M. Ciro, A.K. Abdel Aziz, G. Belmonte, R. Dal Zuffo, C. Mercurio, C. Miracco, L. Lanfrancone, M. Foiani, S. Minucci
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/257707
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