PROCESSING OF HUMAN APOLIPOPROTEIN-B MRNA

大多数脊椎动物的基因被分成多个外显子和内含子； 内含子很大，而外显子则很小。平均大小 脊椎动物的内部外显子有137个核苷酸；很少有超过300个核苷酸的 核苷酸。偶尔也会有较大的外显子存在。这项建议是 关注研究剪接机制是否限制外显子 大小；如果是这样，大的外显子如何绕过正常的限制 剪接过程中的大小；大外显子是否具有功能优势？ 自然产生的一个大的外显子是小鼠的外显子26 人载脂蛋白-b基因。该外显子全长超过7kb。在人类中 肝脏正确拼接产生大的apo-bl00蛋白 512kd参与内源性脂质代谢。在人类中 肠道中，产生包括RNA编辑事件的mRNA。 编辑产生外显子26内的翻译终止密码子；翻译 产生一段252kd的apo-b48蛋白，参与 外源性脂类。编辑伴随外显子内的多聚腺苷酸化 26.本提案描述了旨在了解外显子如何 26在肝脏中被正确识别，或者在 肠子。载脂蛋白-b的调节对正常人群很重要 脂代谢与人类心脏病。对机制的理解 由此产生的两种形式的apo-b应该会增加我们的 关于心脏病的知识以及如何与之抗争。

Most vertebrate genes are split into multiple exons and introns; introns are large; exons, in contrast, are very small. The average size of a vertebrate internal exon is 137 nucleotides; very few exceed 300 nucleotides. Occasionally, large exons exist. This proposal is concerned with investigating if the splicing machinery restricts exon size; if it does, how do large exons by-pass the normal restrictions on size during splicing; and is there a functional advantage to large exons? One naturally occurring large exon is exon 26 of the murine and human apolipoprotein-b gene. This exon is over 7 kb in length. In human liver it is spliced correctly to produce the large apo-bl00 protein of 512 kd involved in the metabolism of endogenous lipids. In human intestine, a mRNA is produced that includes an RNA editing event. Editing produces a translational stop codon within exon 26; translation produces a short apo-b48 protein of 252 kd involved in the metabolism of exogenous lipids. Editing is accompanied by polyadenylation within exon 26. This proposal describes experiments designed to understand how exon 26 is correctly recognized in liver and alternatively recognized in intestine. The regulation of apolipoprotein-b is important to normal lipid metabolism and human heart disease. Understanding the mechanism whereby the two forms of apo-b are generated should increase our knowledge of heart disease and how to combat it.