p27Kip1 signaling: Transcriptional and post-translational regulation
p27Kip1 signaling: Transcriptional and post-translational regulation
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DOI：
10.1016/j.biocel.2015.08.005
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发表时间：
2015-11-01
影响因子：
4
通讯作者：
Dong, Qihan
中科院分区：
文献类型：
--
作者：
Hnit, Su Su Thae;Xie, Chanlu;Dong, Qihan
p27(Kip1) 是一种广谱细胞周期蛋白依赖性激酶 (CDK) 抑制剂，单个 p27(Kip1) 等位基因的丢失足以通过 CDK 介导的细胞周期进入增加肿瘤发生率。因此，p27(Kip1)蛋白水平的下调，特别是核表达的p27(Kip1)，与多种癌症的疾病进展和不良预后有关。 p27(Kip1) 表达受转录因子 MENIN 正向调节，并受致癌转录因子 MYC 和 PIM 抑制。然而，p27(Kip1) 蛋白表达和功能的调节主要是通过翻译后修饰来改变细胞定位和 E3 泛素连接酶介导的降解程度。 p27(Kip1) 在 Thr(187) 和 Ser(10) 处的磷酸化是其分别通过 E3 泛素连接酶 SKP2（核）和 KPC（细胞质）降解的先决条件。此外，由于核输出蛋白 CRM1，Ser(10) 磷酸化 p27(Kip1) 主要位于细胞质中。另一种 E3 泛素连接酶 PIRH2 可降解细胞质和细胞核中的 p27(Kip1)，与磷酸化状态无关。因此，通过旨在纠正 p27(Kip1) 定位和/或阻止其降解的疗法，可以实现对多种癌症的细胞周期进入和进展的抑制。 (C) 2015 Elsevier Ltd. 保留所有权利。
p27(Kip1) is an inhibitor of a broad spectrum of cyclin-dependent kinases (CDKs), and the loss of a single p27(Kip1) allele is thereby sufficient to increase tumor incidence via CDK-mediated cell cycle entry. As such, down-regulation of p27(Kip1) protein levels, in particular nuclear expressed p27(Kip1), is implicated in both disease progression and poor prognosis in a variety of cancers. p27(Kip1) expression is positively regulated by the transcription factor MENIN, and inhibited by oncogenic transcription factors MYC and PIM. However, regulation of p27(Kip1) protein expression and function is predominantly through post-translational modifications that alter both the cellular localization and the extent of E3 ubiquitin ligase-mediated degradation. Phosphorylation of p27(Kip1) at Thr(187) and Ser(10) is a prerequisite for its degradation via the E3 ubiquitin ligases SKP2 (nuclear) and KPC (cytoplasmic), respectively. Additionally, Ser(10) phosphorylated p27(Kip1) is predominantly localized in the cytoplasm due to the nuclear export protein CRM1. Another E3 ubiquitin ligase, PIRH2, degrades p27(Kip1) in both the cytoplasm and nucleus independent of phosphorylation state. As such, inhibition of cell cycle entry and progression in a variety of cancers may be achieved with therapies designed to correct p27(Kip1) localization and/or block its degradation. (C) 2015 Elsevier Ltd. All rights reserved.