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The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis
2017-10
发表期刊JOURNAL OF MOLECULAR CELL BIOLOGY (IF:5.3[JCR-2023],6.1[5-Year])
ISSN1674-2788
卷号9期号:5页码:409-421
发表状态已发表
DOI10.1093/jmcb/mjx028
摘要CDK4 is crucial for G1-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cyclins are pivotal for the timely and unidirectional progression of cell cycle. However, how CDK4 itself is modulated by ubiquitin-mediated degradation has been elusive. Here we report that the steady-state level of CDK4 is controlled by PAQR4, a member of the progestin and adipoQ receptor family, and SKP2, an E3 ubiquitin ligase. Knockdown of PAQR4 leads to reduction of cell proliferation, accompanied by reduced protein level of CDK4. PAQR4 reduces polyubiquitination and degradation of CDK4. PAQR4 interacts with the C-terminal lobe of CDK4. On the other hand, SKP2 also interacts with the C-terminal lobe of CDK4 and enhances polyubiquitination and degradation of CDK4. Importantly, PAQR4 and SKP2 bind to the same region in CDK4, and PAQR4 competes with SKP2 for the binding, thereby abrogating SKP2-mediated ubiquitination of CDK4. Using a two-stage DMBA/TPA-induced skin cancer model, we find that PAQR4-deleted mice are resistant to chemical carcinogen-induced tumor formation. Collectively, our findings reveal that the steady-state level of CDK4 is controlled by the antagonistic actions between PAQR4 and SKP2, contributing to modulation of cell proliferation and tumorigenesis.
关键词CDK4 PAQR4 SKP2 ubiquitination protein degradation tumorigenesis
收录类别SCI ; CSCD
语种英语
资助项目Chinese Academy of Sciences[XDA12010102] ; Chinese Academy of Sciences[QYZDJ-SSW-SMC008] ; Chinese Academy of Sciences[ZDRW-ZS-2016-8]
WOS研究方向Cell Biology
WOS类目Cell Biology
WOS记录号WOS:000417761200007
CSCD记录号CSCD:6136515
出版者OXFORD UNIV PRESS
WOS关键词PHOSPHORYLATION-DEPENDENT UBIQUITINATION ; CELL-CYCLE CONTROL ; F-BOX PROTEINS ; GOLGI-APPARATUS ; S PHASE ; DEGRADATION ; COMPLEX ; LIGASE ; CANCER ; SENESCENCE
原始文献类型Article
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/14307
专题生命科学与技术学院
生命科学与技术学院_特聘教授组_陈雁组
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
通讯作者Chen, Yan
作者单位
1.Univ Chinese Acad Sci, Chinese Acad Sci, CAS Key Lab Nutr & Metab, Inst Nutr Sci,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
2.Tianjin Med Univ Canc Inst & Hosp, Natl Clin Res Ctr Canc, Tianjin Key Lab Canc Immunol & Biotherapy, Canc Mol Diagnost Core Lab, Tianjin 300060, Peoples R China
3.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China
4.Tongji Univ, Dept Clin Med, Shanghai 200092, Peoples R China
通讯作者单位生命科学与技术学院
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GB/T 7714
Wang, Lin,Zhang, Rui,You, Xue,et al. The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis[J]. JOURNAL OF MOLECULAR CELL BIOLOGY,2017,9(5):409-421.
APA Wang, Lin.,Zhang, Rui.,You, Xue.,Zhang, Huanhuan.,Wei, Siying.,...&Chen, Yan.(2017).The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis.JOURNAL OF MOLECULAR CELL BIOLOGY,9(5),409-421.
MLA Wang, Lin,et al."The steady-state level of CDK4 protein is regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis".JOURNAL OF MOLECULAR CELL BIOLOGY 9.5(2017):409-421.
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