Three novel Bid proteins generated by alternative splicing of the human Bid gene.
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.
Academic Units of Respiratory Medicine, University of Sheffield, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, United Kingdom.
Stephen A
SA
Renshaw
Clare E
CE
Dempsey
Frances A
FA
Barnes
Stephanie M
SM
Bagstaff
Steven K
SK
Dower
Colin D
CD
Bingle
Moira K B
MK
Whyte
D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics; D051023:BH3 Interacting Domain Death Agonist Protein; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008969:Molecular Sequence Data; D009928:Organ Specificity; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics
D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger