Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer.
Estrogen and progesterone regulate p27kip1 levels via the ubiquitin-proteasome system: pathogenic and therapeutic implications for endometrial cancer.
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DOI：
10.1371/journal.pone.0046072
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gold LI
中科院分区：
文献类型：
--
作者：
Huang KT;Pavlides SC;Lecanda J;Blank SV;Mittal KR;Gold LI
控制细胞周期的蛋白质水平通过底物特异性的E3泛素连接酶通过泛素-蛋白酶体系统(UPS)调节泛素介导的降解。细胞周期蛋白依赖的激酶抑制因子p27kip1(P27)可被E3连接酶SCF-Skp2/Cks1泛素化，从而被UPS降解。反过来，Skp2和Cks1被E3连接酶复合体APC/CDH1泛素化以进行破坏，从而维持丰富的核p27水平。我们之前的研究表明，p27蛋白酶体的永久性降解是I型子宫内膜癌(ECA)的早期事件，ECA是一种雌激素(E2)诱导的癌症。目前的研究表明，E2刺激Eca细胞株和正常原代子宫内膜上皮细胞(EECs)的生长，并诱导Thr187上依赖MAPK-ERK1/2的p27磷酸化，这是核SCF-Skp2/Cks1泛素化p27和随后降解的先决条件。此外，E2降低了E3连接酶[APC]CDH1，使Skp2和Cks1保持不变，从而导致p27降解。此外，下调Skp2可阻止E2诱导的p27降解和生长刺激，提示E2诱导ECA的发病机制依赖于Skp2介导的p27降解。相反，孕酮(PG)作为子宫内膜增殖的抑制剂，增加了原代EECS和ECA细胞中的核p27和CDH1。PG还可增加CDH1与APC的结合，形成活性E3连接酶。敲除CDH1可消除PG诱导的p27的稳定和生长抑制。值得注意的是，E2和PG都不影响CDH1、Skp2、Cks1和p27的转录。这些研究为激素通过UPS调节细胞增殖提供了新的见解。这些数据表明，通过阻断Skp2/Cks1介导的p27的降解或增加CDH1来介导Skp2-Cks1的降解来阻止核p27的降解是预防和治疗ECA的潜在策略。
The levels of proteins that control the cell cycle are regulated by ubiquitin-mediated degradation via the ubiquitin-proteasome system (UPS) by substrate-specific E3 ubiquitin ligases. The cyclin-dependent kinase inhibitor, p27kip1 (p27), that blocks the cell cycle in G1, is ubiquitylated by the E3 ligase SCF-Skp2/Cks1 for degradation by the UPS. In turn, Skp2 and Cks1 are ubiquitylated by the E3 ligase complex APC/Cdh1 for destruction thereby maintaining abundant levels of nuclear p27. We previously showed that perpetual proteasomal degradation of p27 is an early event in Type I endometrial carcinogenesis (ECA), an estrogen (E2)-induced cancer. The present studies demonstrate that E2 stimulates growth of ECA cell lines and normal primary endometrial epithelial cells (EECs) and induces MAPK-ERK1/2-dependent phosphorylation of p27 on Thr187, a prerequisite for p27 ubiquitylation by nuclear SCF-Skp2/Cks1 and subsequent degradation. In addition, E2 decreases the E3 ligase [APC]Cdh1 leaving Skp2 and Cks1 intact to cause p27 degradation. Furthermore, knocking-down Skp2 prevents E2-induced p27 degradation and growth stimulation suggesting that the pathogenesis of E2-induced ECA is dependent on Skp2-mediated degradation of p27. Conversely, progesterone (Pg) as an inhibitor of endometrial proliferation increases nuclear p27 and Cdh1 in primary EECs and ECA cells. Pg, also increases Cdh1 binding to APC to form the active E3ligase. Knocking-down Cdh1 obviates Pg-induced stabilization of p27 and growth inhibition. Notably, neither E2 nor Pg affected transcription of Cdh1, Skp2, Cks1 nor p27. These studies provide new insights into hormone regulation of cell proliferation through the UPS. The data implicates that preventing nuclear p27 degradation by blocking Skp2/Cks1-mediated degradation of p27 or increasing Cdh1 to mediate degradation of Skp2-Cks1 are potential strategies for the prevention and treatment of ECA.
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DOI：
10.4161/cc.9.5.10914
发表时间：
2010-03-01
期刊：
Cell cycle (Georgetown, Tex.)
影响因子：
--
作者：
Bashir T;Pagan JK;Busino L;Pagano M
通讯作者：
Pagano M
影响因子：
6.4
作者：
Fujita T;Liu W;Doihara H;Wan Y
通讯作者：
Wan Y
影响因子：
64.8
作者：
Bashir, T;Dorrello, NV;Pagano, M
通讯作者：
Pagano, M
影响因子：
14.5
作者：
Bloom, J;Pagano, M
通讯作者：
Pagano, M
影响因子：
--
作者：
Cunha, GR;Cooke, PS;Kurita, T
通讯作者：
Kurita, T