Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.
Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.
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在表达人乳头瘤病毒 E7 的上皮细胞和宫颈癌细胞中，染色质浓缩调节剂 1 通过 Cdk1 废除 G1 细胞周期检查点。
DOI：
10.1038/s41419-018-0584-z
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发表时间：
2018-05-22
影响因子：
9
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Qiao L;Zheng J;Tian Y;Zhang Q;Wang X;Chen JJ;Zhang W
染色质凝聚调节因子1（Regulator of chromatin condensation 1，RCC 1）是Ran GT3的主要鸟嘌呤-核苷酸交换因子，在核质转运、有丝分裂和核膜组装中起关键作用。已知RCC 1是一种重要的细胞周期调节因子，其缺失会导致G1期阻滞，但对这种调节的分子基础知之甚少。此外，人们对RCC 1与癌症之间的关系知之甚少。人乳头瘤病毒（HPV）感染与宫颈癌的发生密切相关。RCC 1在HPV相关性宫颈癌中的表达和功能以及细胞周期调控尚未得到研究。在这项研究中，我们首先观察到RCC 1免疫染色在宫颈癌组织中轻度增加，在HPV E7表达细胞中显著上调;这种定位主要是细胞核。我们发现转录因子c-Jun通过与RCC 1启动子的直接相互作用在转录上上调RCC 1。此外，siRNA介导的RCC 1敲低抑制G1/S细胞周期进程和DNA合成，而RCC 1过表达废除G1检查点。RCC 1敲低通过促进其在HPV E7表达细胞中的降解而下调转录因子E2 F1，尤其是核E2 F1的蛋白水平。E2 F1的过表达挽救了RCC 1敲除介导的G1/S进展抑制。此外，我们发现，细胞周期蛋白依赖性激酶1（Cdk 1），一个已知的E2 F1的目标，参与G1检查点的调节，Cdk 1敲低阻碍G1/S进程，而Cdk 1过表达挽救RCC 1敲低介导的G1细胞周期进程的影响。此外，RCC 1敲低降低了HPV E7蛋白水平，这可能反过来下调E2 F1。我们的研究探讨了RCC 1在G1/S细胞周期进程中的功能，并表明RCC 1可能参与HPV E7介导的基因组不稳定性。
Regulator of chromatin condensation 1 (RCC1) is a major guanine-nucleotide exchange factor for Ran GTPase and plays key roles in nucleo-cytoplasmic transport, mitosis, and nuclear envelope assembly. RCC1 is known to be a critical cell cycle regulator whose loss causes G1 phase arrest, but the molecular basis for this regulation is poorly understood. Furthermore, little is known about the relationship between RCC1 and carcinomas. Human papillomavirus (HPV) infection is highly associated with the development of cervical cancer. The expression and function of RCC1 in HPV-related cervical cancer and cell cycle regulation have not yet been explored. In this study, we first observed that RCC1 immunostaining was mildly increased in cervical cancer tissues and significantly upregulated in HPV E7-expressing cells; this localization was primarily nuclear. We showed that the transcription factor c-Jun transcriptionally upregulates RCC1 via a direct interaction with the RCC1 promoter. Moreover, siRNA-mediated knockdown of RCC1 inhibited G1/S cell cycle progression and DNA synthesis, while overexpression of RCC1 abrogated the G1 checkpoint. RCC1 knockdown downregulated the protein levels of the transcription factor E2F1, especially nuclear E2F1, by promoting its degradation in HPV E7-expressing cells. Overexpression of E2F1 rescued RCC1 knockdown-mediated inhibition of G1/S progression. Additionally, we showed that cyclin-dependent kinase 1 (Cdk1), a known target of E2F1, is involved in G1 checkpoint regulation, as Cdk1 knockdown hindered G1/S progression, while Cdk1 overexpression rescued RCC1 knockdown-mediated effect on G1 cell cycle progression. Furthermore, RCC1 knockdown reduced HPV E7 protein levels, which may in turn downregulate E2F1. Our study explores the function of RCC1 in G1/S cell cycle progression and suggests that RCC1 may be involved in HPV E7-mediated genomic instability.
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