p53 Represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-κB subunit with histone deacetylase 1
p53 Represses cyclin D1 transcription through down regulation of Bcl-3 and inducing increased association of the p52 NF-κB subunit with histone deacetylase 1
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DOI：
10.1128/mcb.23.13.4713-4727.2003
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发表时间：
2003-07-01
影响因子：
5.3
通讯作者：
Perkins, ND
中科院分区：
文献类型：
--
作者：
Rocha, S;Martin, AM;Perkins, ND
p53 和 NF-kappaB 转录因子家族是细胞应激反应的重要多功能调节因子。在这里，我们研究了控制 p53 依赖性细胞周期停滞和与 NF-kappaB 串扰的调节机制。在 H1299 或 U-2 OS 细胞中诱导 p53 后，我们观察到细胞周期蛋白 D1 启动子活性的特异性抑制，与细胞周期蛋白 D1 蛋白和 mRNA 水平的降低相关。这种抑制依赖于细胞周期蛋白 D1 启动子的近端 NF-kappaB 结合位点，该位点已被证明可以结合 p52 NF-kappaB 亚基。 p53 抑制 Bcl-3 蛋白的表达，Bcl-3 蛋白是 IkappaB 家族的成员，作为 p52 NF-kappaB 的转录共激活因子，并且还降低了 p52/Bcl-3 复合物的水平。与此同时，p53 诱导 p52 和组蛋白脱乙酰酶 1 (HDAC1) 的关联显着增加。重要的是，p53 介导的细胞周期蛋白 D1 启动子抑制可通过 Bcl-3 的共表达以及 p52 或脱乙酰酶活性的抑制来逆转。因此，p53 诱导转录开关，其中 p52/Bcl-3 激活剂复合物被 p52/HDAC1 阻遏物复合物取代，从而主动抑制细胞周期蛋白 D1 转录。这些结果揭示了 p53 调节 NF-kappaB 功能和细胞周期进程的独特机制。
The p53 and NF-kappaB transcription factor families are important, multifunctional regulators of the cellular response to stress. Here we have investigated the regulatory mechanisms controlling p53-dependent cell cycle arrest and cross talk with NF-kappaB. Upon induction of p53 in H1299 or U-2 OS cells, we observed specific repression of cyclin D1 promoter activity, correlating with a decrease in cyclin D1 protein and mRNA levels. This repression was dependent on the proximal NF-kappaB binding site of the cyclin D1 promoter, which has been shown to bind the p52 NF-kappaB subunit. p53 inhibited the expression of Bcl-3 protein, a member of the IkappaB family that functions as a transcriptional coactivator for p52 NF-kappaB and also reduced p52/Bcl-3 complex levels. Concomitant with this, p53 induced a significant increase in the association of p52 and histone deacetylase 1 (HDAC1). Importantly, p53-mediated suppression of the cyclin D1 promoter was reversed by coexpression of Bcl-3 and inhibition of p52 or deacetylase activity. p53 therefore induces a transcriptional switch in which p52/Bcl-3 activator complexes are replaced by p52/HDAC1 repressor complexes, resulting in active repression of cyclin D1 transcription. These results reveal a unique mechanism by which p53 regulates NF-kappaB function and cell cycle progression.