Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress.
Regulation of the HDM2-p53 pathway by ribosomal protein L6 in response to ribosomal stress.
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核糖体蛋白 L6 响应核糖体应激对 HDM2-p53 通路的调节
DOI：
10.1093/nar/gkt971
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发表时间：
2014-02
影响因子：
14.9
通讯作者：
Zheng X
中科院分区：
文献类型：
--
作者：
Bai D;Zhang J;Xiao W;Zheng X
HDM 2-p53环对于监测p53水平和人类病理至关重要。因此，鉴定参与该调节环的新分子对于理解p53的动态调节和人类疾病的治疗是必要的。在这里，我们的特征在于，核糖体蛋白L 6结合并抑制HDM 2的E3泛素连接酶活性，随后减弱HDM 2介导的p53多聚泛素化和降解。增强的p53活性进一步减慢细胞周期进程并导致细胞生长抑制。相反，当RPL 6耗尽时，p53的水平显著降低，表明RPL 6对于p53稳定是必需的。我们还发现，在核糖体应激下，RPL 6从核仁转移到核质，这有利于其与HDM 2的结合。RPL 6和HDM 2的相互作用驱动HDM 2介导的RPL 6聚泛素化和蛋白酶体降解。放线菌素D的长期治疗增加了RPL 6泛素化并使RPL 6不稳定，从而使p53反应减弱，直到L 6水平下降。因此，RPL 6和HDM 2形成了一个自动调节反馈环，以监测响应核糖体应激的p53水平。总之，我们的研究确定了RPL 6在调节HDM 2-p53通路中的关键功能，这突出了RPL 6在人类遗传疾病和癌症中的重要性。
The HDM2-p53 loop is crucial for monitoring p53 level and human pathologies. Therefore, identification of novel molecules involved in this regulatory loop is necessary for understanding the dynamic regulation of p53 and treatment of human diseases. Here, we characterized that the ribosomal protein L6 binds to and suppresses the E3 ubiquitin ligase activity of HDM2, and subsequently attenuates HDM2-mediated p53 polyubiquitination and degradation. The enhanced p53 activity further slows down cell cycle progression and leads to cell growth inhibition. Conversely, the level of p53 is dramatically decreased upon the depletion of RPL6, indicating that RPL6 is essential for p53 stabilization. We also found that RPL6 translocalizes from the nucleolus to nucleoplasm under ribosomal stress, which facilitates its binding with HDM2. The interaction of RPL6 and HDM2 drives HDM2-mediated RPL6 polyubiquitination and proteasomal degradation. Longer treatment of actinomycin D increases RPL6 ubiquitination and destabilizes RPL6, and thereby putatively attenuates p53 response until the level of L6 subsides. Therefore, RPL6 and HDM2 form an autoregulatory feedback loop to monitor the level of p53 in response to ribosomal stress. Together, our study identifies the crucial function of RPL6 in regulating HDM2-p53 pathway, which highlights the importance of RPL6 in human genetic diseases and cancers.
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影响因子：
50.3
作者：
Macias E;Jin A;Deisenroth C;Bhat K;Mao H;Lindström MS;Zhang Y
通讯作者：
Zhang Y
影响因子：
3.9
作者：
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Dianzani, Irma
影响因子：
30.8
作者：
Lahav, G;Rosenfeld, N;Alon, U
通讯作者：
Alon, U
影响因子：
4.3
作者：
Barlow, Jillian L.;Drynan, Lesley F.;McKenzie, Andrew N. J.
通讯作者：
McKenzie, Andrew N. J.
影响因子：
64.8
作者：
Ebert, Benjamin L.;Pretz, Jennifer;Bosco, Jocelyn;Chang, Cindy Y.;Tamayo, Pablo;Galili, Naomi;Raza, Azra;Root, David E.;Attar, Eyal;Ellis, Steven R.;Golub, Todd R.
通讯作者：
Golub, Todd R.