Identification and characterization of multiple isoforms of a murine and human tumor suppressor, patched, having distinct first exons
Identification and characterization of multiple isoforms of a murine and human tumor suppressor, patched, having distinct first exons
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DOI：
10.1016/j.ygeno.2004.11.014
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发表时间：
2005-04-01
期刊：
影响因子：
4.4
通讯作者：
Miyashita, T
中科院分区：
文献类型：
--
作者：
Nagao, K;Toyoda, M;Miyashita, T
小鼠和人类patched（PTCH）基因的突变与出生缺陷和癌症有关。PTCH是一种12次跨膜蛋白，是Sonic hedgehog（Shh）信号蛋白的受体。Shh蛋白通过GLI转录因子激活靶基因（包括PTCH）的转录。在此，我们分别鉴定了人和小鼠PTCH mRNA的七种和五种同种型，它们是通过复杂地交替使用五个外显子作为第一外显子（外显子la至le以5 '至3'顺序）产生的。虽然这些亚型的表达谱在人体组织中高度可变，但其中三种，PTCHa，PTCHb和PTCHd，主要在大多数组织中表达，PTCHd是最普遍的。相比之下，PTCHb总是占主导地位，并在E10.5小鼠发育过程中达到最大值。这三种mRNA亚型编码三种具有不同N-末端的PTCH蛋白，PTCHL、PTCHM和PTCHS。这三种异构体的表达受GLI转录因子的调控，并且鉴定出至少两个功能性GLI结合序列，一个在外显子1a中，另一个在外显子1a和外显子1b之间。PTCHL和PTCHM在抑制GLI介导的转录和诱导细胞凋亡方面同样活跃。PTCHS蛋白（由PTCHd编码）缺乏第一个跨膜结构域，比其他两个更不稳定，导致活性降低。这项研究可能揭示了单一PTCH基因在肿瘤细胞生长和胚胎发育中发挥作用的机制。(c)2004爱思唯尔公司All rights reserved.
Mutations in mouse and human patched (PTCH') genes are associated with birth defects and cancer. PTCH, a 12-pass transmembrane protein, is a receptor for Sonic hedgehog (Shh) signaling proteins. Shh proteins activate transcription of target genes, including PTCH, via GLI transcription factors. Here we identified seven and five isoforms of human and mouse PTCH mRNA, respectively, which are generated by the complex alternative use of five exons as the first exon (exons la to le in the 5'-to-3' order). Although expression profiles of these isoforms were highly variable among human tissues, three of them, PTCHa, PTCHb, and PTCHd, were predominantly expressed in most tissues, PTCHd being most ubiquitous. In contrast, PTCHb was always predominant and reached a maximum at E10.5 during mouse development. These three mRNA isoforms encode three PTCH proteins with distinct N-termini, PTCHL, PTCHM, and PTCHS. The expression of these three isoforms was regulated by GLI transcription factors, and at least two functional GLI-binding sequences were identified, one in exon 1a and the other between exon 1a and exon 1b. PTCHL and PTCHM were equally active in terms of suppressing GLI-mediated transcription and inducing apoptosis. PTCHS protein (encoded by PTCHd), lacking the first transmembrane domain, was more unstable than the other two, resulting in a reduced activity. This study may shed light on the mechanism whereby a single PTCH gene plays a role in both tumor cell growth and embryonic development. (c) 2004 Elsevier Inc. All rights reserved.