Btf, a novel death-promoting transcriptional repressor that interacts withBcl-2-related proteins

The adenovirus E1B 19,000 molecular-weight (19K) protein is a potent inhibi tor of apoptosis and cooperates with E1A to transform primary rodent cells. E1B 19K shows sequence and functional homology to the mammalian antiapopto tic gene product, Bcl-2, Like Bcl-2, the biochemical mechanism of E1B 19K f unction includes binding to and antagonization of cellular proapoptotic pro teins such as pax, Bak, and Nbk/Bik In addition, there is evidence that E1B 19K can affect gene expression, but whether this contributes to its antiap optotic function has not been determined. In an effort to further understan d the functions of E1B 19K, we screened for 19K-associated proteins by the yeast two-hybrid system. A novel protein, Btf (Bcl-2-associated transcripti on factor), that interacts with E1B 19K as well as with the antiapoptotic f amily members Bcl-2 and Bcl-x(L) but not with the proapoptotic protein Bar was identified. btf is a widely expressed gene that encodes a protein with homology to the basic zipper (bZip) and Myb DNA binding domains. Btf binds DNA in vitro and represses transcription in reporter assays. E1B 19K, Bcl-2 , and Bcl-x(L) sequester Btf in the cytoplasm and block its transcriptional repression activity, Expression of Btf also inhibited transformation by EI A with either E1B 19K or mutant p53, suggesting a role in either promotion of apoptosis or cell cycle arrest. Indeed, the sustained overexpression of Btf in HeLa cells induced apoptosis, which was inhibited by E1B 19K. Furthe rmore, the chromosomal localization of btf (6q22-23) maps to a region that is deleted in some cancers, consistent with a role for Btf in tumor suppres sion. Thus, btf may represent a novel tumor suppressor gene residing in a u nique pathway by which the Bcl-2 family can regulate apoptosis.