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首页> 外文期刊>Genomics >Identification and characterization of multiple isoforms of a murine and human tumor suppressor, patched, having distinct first exons.
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Identification and characterization of multiple isoforms of a murine and human tumor suppressor, patched, having distinct first exons.

机译：小鼠和人类抑癌药的多种同工型的鉴定和表征，已修补，具有不同的第一个外显子。

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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 1a to 1e 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, PTCH(L), PTCH(M), and PTCH(S). 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. PTCH(L) and PTCH(M) were equally active in terms of suppressing GLI-mediated transcription and inducing apoptosis. PTCH(S) 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.
机译：小鼠和人类补丁（PTCH）基因的突变与出生缺陷和癌症有关。 PTCH是一种12遍跨膜蛋白，是Sonic刺猬（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。在这里，我们分别确定了人类和小鼠PTCH mRNA的7种和5种同工型，它们是通过复杂交替使用5个外显子作为第一个外显子（从5'到3'的顺序从1a到1e）生成的。尽管这些同工型的表达谱在人体组织中高度可变，但其中的三个，PTCHa，PTCHb和PTCHd主要在大多数组织中表达，其中PTCHd最普遍。相反，在小鼠发育过程中，PTCHb始终占主导地位，在E10.5达到最大值。这三个mRNA同工型编码具有不同N末端的三个PTCH蛋白，PTCH（L），PTCH（M）和PTCH（S）。这三种同工型的表达受GLI转录因子调控，并且至少鉴定出两个功能性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。就抑制GLI介导的转录和诱导细胞凋亡而言，PTCH（L）和PTCH（M）具有同等活性。缺少第一个跨膜结构域的PTCH（S）蛋白（由PTCHd编码）比其他两个结构域更加不稳定，从而导致活性降低。这项研究可能揭示单个PTCH基因在肿瘤细胞生长和胚胎发育中均起作用的机制。

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