Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2
Program in Molecular Medicine; Program in Gene Function and Expression
Apoptosis; Cell Cycle Proteins; Cell Line, Tumor; Fibroblasts; Hela Cells; Humans; Mitochondrial Proteins; NF-kappa B; Neoplasms; Protein Binding; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2; Transcriptional Activation; Tumor Necrosis Factor-alpha; bcl-2-Associated X Protein
Life Sciences | Medicine and Health Sciences
The Bcl-2 family of proteins consists of both antiapoptotic and proapoptotic factors, which share sequence homology within conserved regions known as Bcl-2 homology domains. Interactions between Bcl-2 family members, as well as with other proteins, regulate apoptosis through control of mitochondrial membrane permeability and release of cytochrome c. Here we identify a novel regulator of apoptosis that lacks Bcl-2 homology domains but acts by binding Bcl-2 and modulating its antiapoptotic activity. To identify regulators of apoptosis, we performed expression profiling in human primary fibroblasts treated with tumor necrosis factor-alpha (TNF-alpha), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-kappaB. We found that the gene undergoing maximal transcriptional induction following TNF-alpha treatment was G(0)-G(1) switch gene 2 (G0S2), the activation of which also required NF-kappaB. We show that G0S2 encodes a mitochondrial protein that specifically interacts with Bcl-2 and promotes apoptosis by preventing the formation of protective Bcl-2/Bax heterodimers. We further show that ectopic expression of G0S2 induces apoptosis in diverse human cancer cell lines in which endogenous G0S2 is normally epigenetically silenced. Our results reveal a novel proapoptotic factor that is induced by TNF-alpha through NF-kappaB and that interacts with and antagonizes Bcl-2.
DOI of Published Version
Cancer Res. 2009 Sep 1;69(17):6782-9. Epub 2009 Aug 25. Link to article on publisher's site
Welch, Christian; Santra, Manas K.; El-Assaad, Wissal; Zhu, Xiaochun; Huber, Wade E.; Keys, Richard A.; Teodoro, Jose G.; and Green, Michael R., "Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2" (2009). Open Access Articles. 2104.