Regulation of the cell death program involves physical interactions between different members of the Bcl‐2 family that either promote or suppress apoptosis. The Bcl‐2 homolog, Bak, promotes apoptosis and binds anti‐apoptotic family members including Bcl‐2 and Bcl‐xL. We have identified a domain in Bak that is both necessary and sufficient for cytotoxic activity and binding to Bcl‐xL. Sequences similar to this domain were identified in Bax and Bip1, two other proteins that promote apoptosis and interact with Bcl‐xL, and were likewise critical for their capacity to kill cells and bind Bcl‐xL. Thus, the domain is of central importance in mediating the function of multiple cell death‐regulatory proteins that interact with Bcl‐2 family members.
BH3-only proteins function at a proximal point in a conserved cell death pathway by binding, through their BH3 domains, to other Bcl-2 family members and triggering mitochondrial events associated with apoptosis. Here, we describe a strongly pro-apoptotic BH3-only protein, designated Bbc3, whose expression increases in response to diverse apoptotic stimuli. bbc3 mRNA levels were induced by exposure to DNA-damaging agents and by wild-type p53, which mediates DNA damage-induced apoptosis. p53 transactivated bbc3 through consensus p53 binding sites within the bbc3 promoter region, indicating that bbc3 is a direct target of p53. Additionally, bbc3 mRNA was induced by p53-independent apoptotic stimuli, including dexamethasone treatment of thymocytes, and serum deprivation of tumor cells. Insulin-like growth factor-1 and epidermal growth factor, growth factors with broad anti-apoptotic activity, were each sufficient to suppress Bbc3 expression in serum-starved tumor cells. These results suggest that the transcriptional regulation of bbc3 contributes to the transduction of diverse cell death and survival signals.
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