title: A novel autophagy-independent, oncosuppressive function of BECN1: Degradation of MCL1.
abstract: The discovery that heterozygous disruption of Becn1 in mice leads to spontaneous tumor development was the first direct link arguing for a predominantly tumor-suppressor function of autophagy. However, the mechanisms by which BECN1 restrains tumorigenesis and whether autophagy-independent functions of BECN1 contribute to its tumor-restraining potential remained unexplored. We recently described a novel function of BECN1-regulation of oncogene MCL1 protein levels. Our results show that BECN1 regulates MCL1 levels in an inverse-reciprocal manner, whereby changes in the levels of one of the 2 proteins inversely affects the proteasomal degradation of the other. Importantly, this mechanism is independent of autophagy and of the physical interaction between BECN1 and MCL1. In vitro and in vivo analysis using several models, including patient-derived melanoma cells and tissue samples from patients with melanocytic lesions at different stages, showed that the identified mechanism of inverse coregulation between BECN1 and MCL1 significantly contributes to their opposing roles in tumorigenesis.
authors.affiliation: a Department of Experimental Oncology ; European Institute of Oncology ; IEO ; Milan , Italy.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgendy
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001343:Autophagy; D000071186:Beclin-1; D063646:Carcinogenesis; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006579:Heterozygote; D006801:Humans; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000196:embryology; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D009857:Oncogenes; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; C115010:Becn1 protein, mouse; C579095:MCL1 protein, human; C579094:Mcl1 protein, mouse; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C506234:USP9X protein, human; D010450:Endopeptidases; D043222:Ubiquitin Thiolesterase; C404328:Usp9x protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: BECN1; MCL1; USP9X; melanoma; proteasome