Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter.
Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter.
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发表时间：
2002
影响因子：
5.3
通讯作者：
T. Nakagawa;M. Takahashi;T. Ozaki;Ken-ichi Watanabe Ki;S. Todo;H. Mizuguchi;T. Hayakawa;A. Nakagawara-A.
中科院分区：
文献类型：
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作者：
T. Nakagawa;M. Takahashi;T. Ozaki;Ken-ichi Watanabe Ki;S. Todo;H. Mizuguchi;T. Hayakawa;A. Nakagawara-A.
p73是一种与p53相关的肿瘤抑制基因，但也可被癌基因产物如E2F-1诱导，这就提出了p73是肿瘤抑制基因还是癌基因的问题。与p53不同，p73有几种变体，包括Delta Np73，它缺乏NH(2)末端的反激活结构域。尽管在发育中的神经元中，Delta Np73大量表达，似乎抑制了p53的促凋亡功能，但p73和Delta Np73在细胞生长和分化中的作用及其调控机制尚不清楚。在这里，我们报道了p73，而不是p53，通过结合位于Delta Np73启动子区域-76至-57位置的p73特异性靶元件直接激活内源性Delta Np73的转录。p63对Np73启动子的激活是边缘性的。正如免疫沉淀试验所证明的那样，Delta Np73与p73 α、p73 β和p53相关，当我们在SAOS-2细胞中使用Mdm2、Bax或Delta Np73本身的报告基因时，Delta Np73抑制了它们的反活化活性。此外，诱导或过表达Delta Np73通过与p53和p73本身竞争来促进细胞存活。因此，我们的研究结果表明，p73的靶细胞Delta Np73的负反馈调控是一种新的调节细胞生存和死亡的自调节系统。
p73 is a p53-related tumor suppressor but is also induced by oncogene products such as E2F-1, raising a question as to whether p73 is a tumor suppressor gene or oncogene. Unlike p53, p73 has several variants, including Delta Np73, which lacks the NH(2)-terminal transactivation domain. Although, in developing neurons, Delta Np73 is expressed abundantly and seems to inhibit the proapoptotic function of p53, the role of p73 and Delta Np73 and their regulatory mechanism in cell growth and differentiation are poorly understood. Here we report that p73, but not p53, directly activates the transcription of endogenous Delta Np73 by binding to the p73-specific target element located at positions -76 to -57 within the Delta Np73 promoter region. The activation of Delta Np73 promoter by p63 was marginal. Delta Np73 was associated with p73 alpha, p73 beta, and p53, as demonstrated by immunoprecipitation assays, and inhibited their transactivation activities when we used reporters of Mdm2, Bax, or Delta Np73 itself in SAOS-2 cells. Furthermore, induction or overexpression of Delta Np73 promoted cell survival by competing with p53 and p73 itself. Thus, our results suggest that the negative feedback regulation of p73 by its target Delta Np73 is a novel autoregulatory system for modulating cell survival and death.