Transcriptional activities of p73 splicing variants are regulated by inter-variant association.
Transcriptional activities of p73 splicing variants are regulated by inter-variant association.
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DOI：
10.1042/0264-6021:3560859
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发表时间：
2001-06
期刊：
影响因子：
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通讯作者：
Y. Ueda;M. Hijikata;S. Takagi;T. Chiba;K. Shimotohno
中科院分区：
文献类型：
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作者：
Y. Ueda;M. Hijikata;S. Takagi;T. Chiba;K. Shimotohno
p73已被鉴定为编码与肿瘤抑制因子p53具有显著同一性的蛋白质的基因。p73和p53之间的主要结构差异是p73的额外C末端区域。已经报道了具有不同C-末端结构的六种p73同种型，α、β、γ、δ、β和xi。这些变体在p53应答启动子上的转录活性不同。在这里，我们报告一个可能的机制，转录激活p73剪接变异体。p73 α的C-末端缺失突变体显示出比野生型p73 α显著更高水平的转录活性，表明p73 α的C-末端结构起抑制p73 α的转录活性的作用。在哺乳动物细胞中的免疫沉淀试验和双杂交试验的结果表明，p73变体相互作用，但不与p53。p73 β的转录活性通过与p73 α或p73 β共表达而降低，p73 α或p73 β具有与p73 α相同的C末端结构。p73 α或p73 β的C-末端部分与p73 β的共表达也导致转录活性降低。此外，我们观察到，p73 β诱导的内源性p21蛋白的水平通过共表达全长p73 β或p73 α或p73 β的C-末端区域而降低。这些观察结果表明，p73介导的基因表达的调节p73剪接变异体在细胞中的相互作用。
p73 has been identified as a gene that encodes a protein with significant identity with the tumour suppressor p53. The main structural difference between p73 and p53 is the additional C-terminal region of p73. Six isoforms of p73 with differing C-terminal structures, alpha, beta, gamma, delta, epsilon and xi, have been reported. These variants differ in transcriptional activity on p53-responsive promoters. Here we report a possible mechanism of transcriptional activation by p73 splicing variants. C-terminal deletion mutants of p73 alpha showed a significantly higher level of transcriptional activity than wild-type p73 alpha, suggesting that the C-terminal structure of p73 alpha functions to repress the transcriptional activity of p73 alpha. The results of immunoprecipitation assays and two-hybrid assays in mammalian cells showed that the p73 variants interacted with each other, but not with p53. The transcriptional activity of p73 beta was reduced by co-expression with either p73 alpha or p73 epsilon, which bears an identical C-terminal structure to p73 alpha. Co-expression of the C-terminal portion of p73 alpha or p73 epsilon with p73 beta also resulted in reduced transcriptional activity. Moreover, we observed that the level of endogenous p21 protein induced by p73 beta was decreased by co-expression of full-length p73 epsilon or the C-terminal region of p73 alpha or p73 epsilon. These observations suggest that p73-mediated gene expression is regulated by the interactions of p73 splicing variants in the cell.