An isoform of ZBP-89 predisposes the colon to colitis
An isoform of ZBP-89 predisposes the colon to colitis
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DOI：
10.1093/nar/gkl022
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发表时间：
2006-01-01
影响因子：
14.9
通讯作者：
Merchant, JL
中科院分区：
文献类型：
--
作者：
Law, DJ;Labut, EM;Merchant, JL
选择性剪接使得功能多样的蛋白质同种型能够表达。锌指转录因子ZBP-89的结构和功能的复杂性表明，它可能是一类选择性剪接基因。我们鉴定了人ZBP-89剪接异构体（ZBP-89（Delta N）），其缺少全长蛋白（ZBP-89（FL））的氨基末端残基1-127。ZBP-89（Delta N）mRNA与其ZBP-89（FL）同源物在胃肠道细胞系和组织中共表达。类似地，表达ZBP-89（Delta N）蛋白。为了确定其在体内的功能，我们通过靶向编码氨基末端的外显子4来产生ZBP-89（Delta N）敲入小鼠。纯合子ZBP-89（Delta N）小鼠，仅表达ZBP-89（Delta N）蛋白，经历生长延迟、活力降低和对葡聚糖硫酸钠结肠炎的易感性增加。我们得出结论，ZBP-89（Δ N）拮抗ZBP-89（FL）的功能，截短的异构体的过度表达破坏胃肠道的稳态。
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(Delta N)), which lacks amino terminal residues 1-127 of the full-length protein (ZBP-89(FL)). ZBP-89(Delta N) mRNA was co-expressed with its ZBP-89(FL) cognate in gastrointestinal cell lines and tissues. Similarly, ZBP-89(Delta N) protein was expressed. To define its function in vivo, we generated ZBP-89(Delta N) knock-in mice by targeting exon 4 that encodes the amino terminus. Homozygous ZBP-89(Delta N) mice, expressing only ZBP-89(Delta N) protein, experienced growth delay, reduced viability and increased susceptibility to dextran sodium sulfate colitis. We conclude that ZBP-89(Delta N) antagonizes ZBP-89(FL) function and that over-expression of the truncated isoform disrupts gastrointestinal homeostasis.