We have cloned the cDNAs for two novel human proteins, designated BNIP-S␣ and ␤ (for BNIP-2 Similar) that are homologous to BNIP-2, a previously known Bcl-2 and E1B-associated protein. The BNIP-S gene encodes two protein isoforms; the longer protein (BNIP- S␣) contains a complete BNIP-2 and Cdc42GAP Homology (BCH) domain, a novel protein domain that we recently identified, whereas its shorter variant (BNIP-S␤) lacks the full BCH domain as a result of an alternative RNA splicing that introduces

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... nonsense intron. Primer-specific reverse-transcription PCR revealed that both BNIP-S␣ and BNIP-S␤ mRNA are differentially expressed in various cells and tissues. The expression of BNIP-S␣ or the complete BCH domain, but not BNIP-S␤, causes extensive apoptosis in cells. Furthermore, BNIP-S␣ can form a homophilic complex via a unique sequence motif within its BCH domain, and deletion of this interacting motif prevents its pro-apoptotic effect. These results indicate the presence of two BNIP-S splicing variants as cellular regulators and that the BCH domain of BNIP-S␣ confers a novel apoptotic function. The significance of this is discussed.