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J. Biol. Chem., Vol. 279, Issue 4, 2846-2855, January 23, 2004

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Three Novel Bid Proteins Generated by Alternative Splicing of the Human Bid Gene^*

Stephen A. Renshaw, Clare E. Dempsey, Frances A. Barnes, Stephanie M. Bagstaff¶, Steven K. Dower¶, Colin D. Bingle, and Moira K. B. Whyte||

From the Academic Units of Respiratory Medicine and ^¶Cell Biology, Section of Functional Genomics, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom

Bid, a BH3-only Bcl-2 protein, is activated by proteolytic cleavage exposing the BH3 domain, which then induces apoptosis by interacting with pro-apoptotic Bcl-2 family proteins (e.g. Bax and Bak) at the mitochondrial surface. The arrangement of domains within Bid suggested that Bid function might be regulated in part by alternative splicing. We have determined the gene structure of human Bid and identified a number of novel exons. We have also demonstrated endogenous mRNA and protein expression for three novel isoforms of Bid, generated using these exons. Bid_S contains the N-terminal regulatory domains of Bid without the BH3 domain; Bid_EL corresponds to full-length Bid with additional N-terminal sequence; and Bid_ES contains only the Bid sequence downstream of the BH3 domain. Expression of these isoforms is regulated during granulocyte maturation. In functional studies Bid_EL induces apoptosis, whereas Bid_S abrogates the pro-apoptotic effects of truncated Bid and inhibits Fas-mediated apoptosis. Bid_ES induces apoptosis but is also able to partially inhibit the pro-apoptotic effects of truncated Bid. These three novel endogenously expressed isoforms of Bid are distinct in their expression, their cellular localization, and their effects upon cellular apoptosis. Differential expression of these novel Bid isoforms may regulate the function of Bid following cleavage and thus influence the fate of cells exposed to a range of pro-apoptotic stimuli.

Received for publication, September 3, 2003 , and in revised form, October 6, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AY005151 and AF250233.

^* This work was supported by Wellcome Trust Medical Graduate Fellowship 055730 (to S. A. R.) and a British Heart Foundation Studentship (to F. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Academic Unit of Respiratory Medicine, Division of Genomic Medicine, University of Sheffield, Royal Hallamshire Hospital, Sheffield S10 2JF, UK. Tel.: 44-114-271-2196; Fax: 44-114-272-1104; E-mail: m.k.whyte{at}sheffield.ac.uk.

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