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.
|Titolo:||Beclin 1 restrains tumorigenesis through Mcl-1 destabilization in an autophagy-independent reciprocal manner|
FOIANI, MARCO (Penultimo)
MINUCCI, SAVERIO (Corresponding)
|Parole Chiave:||targeting MCL-1; prostate-cancer; melanoma-cells; apoptosis; expression; resistance; survival; therapy; inhibition; sabutoclax|
|Settore Scientifico Disciplinare:||Settore BIO/11 - Biologia Molecolare|
|Data di pubblicazione:||2014|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/ncomms6637|
|Appare nelle tipologie:||01 - Articolo su periodico|