UV-dependent alternative splicing uncouples p53 activity and PIG3 gene function through rapid proteolytic degradation
UV-dependent alternative splicing uncouples p53 activity and PIG3 gene function through rapid proteolytic degradation
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DOI：
10.1074/jbc.m401049200
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发表时间：
2004-06-04
影响因子：
4.8
通讯作者：
Beattie, TL
中科院分区：
文献类型：
--
作者：
Nicholls, CD;Shields, MA;Beattie, TL
p53 诱导基因 3 (PIG3) 是肿瘤抑制蛋白 p53 的转录靶标，被认为在细胞凋亡中发挥作用。在本报告中，我们从 PIG3 基因中鉴定出一种新型选择性剪接产物，我们称之为 PIG3AS（PIG3 选择性剪接）。 PIG3AS 是由选择性前 mRNA 剪接产生的，该剪接跳过了 PIG3 转录物中包含的五个外显子中的外显子 4。所得蛋白质产物与 PIG3 共享前 206 个氨基酸，但具有独特的 42 个氨基酸 C 末端。在未受应激的细胞中，在大多数诱导 PIG3 基因转录的 DNA 损伤条件下，PIG3 转录物的产生占主导地位。然而，响应紫外线，前体 mRNA 剪接发生显着变化，有利于 PIG3AS。与PIG3蛋白不同，PIG3AS蛋白降解迅速，半衰期短，并通过蛋白酶体抑制而稳定。我们的结果说明了内源性、紫外线诱导的选择性剪接事件的第一个例子，并且剪接机制的控制参与了细胞 DNA 损伤反应。他们还表明，快速蛋白水解降解代表了一种将 p53 活性与 PIG3 基因激活解偶联的细胞机制，该机制与启动子选择性无关。
The p53-inducible gene 3 (PIG3) is a transcriptional target of the tumor suppressor protein p53 and is thought to play a role in apoptosis. In this report, we identify a novel alternatively spliced product from the PIG3 gene that we call PIG3AS ( PIG3 alternative splice). PIG3AS results from alternative pre-mRNA splicing that skips exon 4 of the five exons included in the PIG3 transcript. The resulting protein product shares its first 206 amino acids with PIG3 but has a unique 42-amino acid C terminus. In unstressed cells and after most DNA damage conditions that induce transcription from the PIG3 gene, production of the PIG3 transcript dominates. However, in response to UV light, pre-mRNA splicing shifts dramatically in favor of PIG3AS. Unlike the PIG3 protein, the PIG3AS protein is rapidly degraded with a short half-life and is stabilized by proteasome inhibition. Our results illustrate the first example of an endogenous, UV-inducible, alternative splicing event and that control of the splicing machinery is involved in the cellular DNA damage response. They also suggest that rapid proteolytic degradation represents a cellular mechanism for uncoupling p53 activity from PIG3 gene activation that is independent of promoter selectivity.