Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase
Phosphorylation-dependent ubiquitylation and degradation of androgen receptor by Akt require Mdm2 E3 ligase
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DOI：
10.1093/emboj/cdf406
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发表时间：
2002-08-01
期刊：
影响因子：
11.4
通讯作者：
Chang, CS
中科院分区：
文献类型：
--
作者：
Lin, HK;Wang, L;Chang, CS
雄激素受体（AR）控制着多种生物学功能，包括前列腺细胞的生长和凋亡。然而，AR维持其稳定性以正常运作的机制在很大程度上仍然未知。我们发现Akt和Mdm2与AR形成复合物，促进磷酸化依赖性AR泛素化，导致AR被蛋白酶体降解。与野生型细胞系相比，在Mdm2缺失的细胞系中，Akt对AR泛素化和降解的影响明显减弱，这表明Mdm2参与了Akt介导的AR泛素化和降解。此外，我们证明了Mdm2的E3连接酶活性和Akt对Mdm2的磷酸化是Mdm2影响AR泛素化和降解的必要条件。这些结果表明，磷酸化依赖的AR泛素化和Akt的降解需要Mdm2 E3连接酶活性的参与，这是一种新的机制，可以深入了解AR是如何被降解的。
The androgen receptor (AR) controls several biological functions including prostate cell growth and apoptosis. However, the mechanism by which AR maintains its stability to function properly remains largely unknown. Here we show that Akt and Mdm2 form a complex with AR and promote phosphorylation-dependent AR ubiquitylation, resulting in AR degradation by the proteasome. The effect of Akt on AR ubiquitylation and degradation is markedly impaired in a Mdm2-null cell line compared with the wild-type cell line, suggesting that Mdm2 is involved in Akt-mediated AR ubiquitylation and degradation. Furthermore, we demonstrate that the E3 ligase activity of Mdm2 and phosphorylation of Mdm2 by Akt are essential for Mdm2 to affect AR ubiquitylation and degradation. These results suggest that phosphorylation-dependent AR ubiquitylation and degradation by Akt require the involvement of Mdm2 E3 ligase activity, a novel mechanism that provides insight into how AR is targeted for degradation.