Identification of a protein, G0S2, that lacks Bcl-2 homology domains and interacts with and antagonizes Bcl-2.
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.
Welch
Christian
C
Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
Santra
Manas K
MK
El-Assaad
Wissal
W
Zhu
Xiaochun
X
Huber
Wade E
WE
Keys
Richard A
RA
Teodoro
Jose G
JG
Green
Michael R
MR
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D018797:Cell Cycle Proteins; C508073:G0S2 protein, human; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein
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