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Identification of a Protein, G0S2, That Lacks Bcl-2 Homology Domains and Interacts with and Antagonizes Bcl-2

¹ Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts and ² Goodman Cancer Centre and Department of Biochemistry, McGill University, Montreal, Quebec, Canada

Requests for reprints: Jose G. Teodoro, Goodman Cancer Centre, McGill University, 1160 Pine Avenue, Room 616, Montreal, Quebec, Canada H3A 1A3. Phone: 514-398-3273; Fax: 514-398-6769; E-mail: jose.teodoro{at}mcgill.ca or Michael R. Green, Howard Hughes Medical Institute, Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605. Phone: 508-856-5330; Fax: 508-856-5473; E-mail: michael.green{at}umassmed.edu.

Key Words: apoptosis • Bcl-2 • G0S2 • NF-B • TNF-

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- (TNF-), a potent inflammatory cytokine that can regulate apoptosis and functions, at least in part, by inducing expression of specific genes through NF-B. We found that the gene undergoing maximal transcriptional induction following TNF- treatment was G₀-G₁ switch gene 2 (G0S2), the activation of which also required NF-B. 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- through NF-B and that interacts with and antagonizes Bcl-2. [Cancer Res 2009;69(17):6782–9]