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PMID: 29789527 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

Regulator of chromatin condensation 1 abrogates the G1 cell cycle checkpoint via Cdk1 in human papillomavirus E7-expressing epithelium and cervical cancer cells.

Cell death & disease ·Vol. 9 ·No. 6 ·2018-00-22 ·Pages 583

Qiao L, Zheng J, Tian Y, Zhang Q, Wang X, Chen JJ, Zhang W

Abstract

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.

MeSH Terms
3T3 Cells Animals CDC2 Protein Kinase/metabolism Cell Cycle Proteins/genetics,metabolism Cell Line, Tumor DNA Replication E2F1 Transcription Factor/metabolism Female G1 Phase Cell Cycle Checkpoints Gene Expression Regulation, Neoplastic Guanine Nucleotide Exchange Factors/genetics,metabolism Humans Mice Nuclear Proteins/genetics,metabolism Papillomavirus E7 Proteins/metabolism Proteolysis Up-Regulation/genetics Uterine Cervical Neoplasms/metabolism,pathology,virology
Chemicals
Cell Cycle Proteins E2F1 Transcription Factor Guanine Nucleotide Exchange Factors Nuclear Proteins Papillomavirus E7 Proteins RCC1 protein, human CDC2 Protein Kinase CDK1 protein, human
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Qiao Lijun
Cancer Research Center and Department of Microbiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Zheng Jingyi
Department of Microbiology and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Tian Yonghao
Department of Orthopedic Surgery, Qilu Hospital Affiliated Shandong University, Jinan, Shandong, China.
Zhang Qishu
Cancer Research Center and Department of Microbiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Wang Xiao
Institute of Pathobiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Chen Jason J
Cancer Research Center and Department of Microbiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China.
Zhang Weifang
Department of Microbiology and Key Laboratory of Infection and Immunity of Shandong Province, School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China. zhangweifang@sdu.edu.cn.
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Article Info
Journal
Cell death & disease
Abbr.
Cell Death Dis
ISSN
2041-4889
DOI
10.1038/s41419-018-0584-z
Email
zhangweifang@sdu.edu.cn
Published
2018-00-22
Epub
2018-00-22
Pages
583
Language
English
Region
England
NLM ID
101524092
PMCID
PMC5964113
Subset
IM
External Links
PubMed source DOI: 10.1038/s41419-018-0584-z PMC Full Text View journal details
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