An isoform of ZBP-89 predisposes the colon to colitis.
Alternative splicing enables expression of functionally diverse protein isoforms. The structural and functional complexity of zinc-finger transcription factor ZBP-89 suggests that it may be among the class of alternatively spliced genes. We identified a human ZBP-89 splice isoform (ZBP-89(DeltaN)), which lacks amino terminal residues 1-127 of the full-length protein (ZBP-89(FL)). ZBP-89(DeltaN) mRNA was co-expressed with its ZBP-89(FL) cognate in gastrointestinal cell lines and tissues. Similarly, ZBP-89(DeltaN) protein was expressed. To define its function in vivo, we generated ZBP-89(DeltaN) knock-in mice by targeting exon 4 that encodes the amino terminus. Homozygous ZBP-89(DeltaN) mice, expressing only ZBP-89(DeltaN) protein, experienced growth delay, reduced viability and increased susceptibility to dextran sodium sulfate colitis. We conclude that ZBP-89(DeltaN) antagonizes ZBP-89(FL) function and that over-expression of the truncated isoform disrupts gastrointestinal homeostasis.
Law
David J
DJ
Department of Internal Medicine, University of Michigan, 1150 W. Medical Center Dr., MSRB I, Rm. 3510, Ann Arbor, MI 48109-0650, USA.
Labut
Edwin M
EM
Adams
Rachael D
RD
Merchant
Juanita L
JL
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D003092:Colitis / Q000139:chemically induced / Q000209:etiology* / Q000473:pathology; D003106:Colon / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D016264:Dextran Sulfate; D005091:Exons; D005260:Female; D018390:Gene Targeting; D006130:Growth Disorders / Q000209:etiology; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D002679:Pan troglodytes; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016019:Survival Analysis; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; C110951:ZNF148 protein, human; C491741:Zfp148 protein, mouse; D016264:Dextran Sulfate