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The steady-state level of CDK4 protein ms regulated by antagonistic actions between PAQR4 and SKP2 and involved in tumorigenesis

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Journal of Molecular Cell Biology 2017年第5期9卷 409-421页

作者： Lin Wang RuiZhang Xue You Huanhuan Zhang Siying Wei Tingting Cheng Qianqian Gao zhenzhenwang Yan Chen CAS Key Laboratory of Nutrition and Metabolism Institute for Nutritional Sciences Shanghai Academy of Sciences Chinese Academy of Sciences Shanghai 200031 China Cancer Molecular Diagnostic Core Laboratory Tianjin Medical University Cancer Institute and Key Laboratory of Cancer Immunology and Biotherapy Tianjin 300060 China School of Life Sciences and Technology ShanghaiTech University Shanghai 200031 China Department of Clinical Medicine Tongji University Shanghai 200092 China Department of Clinical Medicine Tongji University Shanghai 200092 China

CDK4 is crucial for Gl-to-S transition of cell cycle. It is well established that ubiquitin-mediated degradations of CDK inhibitors and cycUns 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

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Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer

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Protein & Cell 2016年第2期7卷 141-151页

作者： Haiyang Zhang Jingjing Duan Yanjun Qu Ting Deng Rui Liu Le Zhang Ming Bai Jialu Li Tao Ning Shaohua Ge Xia Wang zhenzhenwang~ Qian Fan Hongli Li Guoguang Ying Dingzhi Huang Yi Ba Tianjin Medical University Cancer Institute and Hospital Key Laboratory of Cancer Prevention and Therapy National ClinicalResearch Center for Cancer Tianjin 300060 China Department of Gastroenterology Tianjin First Center Hospital Tianjin 300192 China Changchun GeneScience Pharmaceuticals Co. Ltd Changchun 130012 China

Gastric cancer is one of the most common malignancies worldwide; however, the molecular mechanism in tumorigenesis still needs exploration. BCL2L11 belongs to the BCL-2 family, and acts as a central regulator of the intrinsic apoptotic cascade and mediates cell apoptosis. Although miRNAs have been reported to be involved in each stage of cancer development, the role of miR-24 in GC has not been reported yet. In the present study, miR- 24 was found to be up-regulated while the expression of BCL2L11 was inhibited in tumor tissues of GC. Studies from both in vitro and in vivo shown that miR-24 regulates BCL2L11 expression by directly binding with 3＇UTR of mRNA, thus promoting cell growth, migration while inhibiting cell apoptosis. Therefore, miR-24 is a novel onco-miRNA that can be potential drug targets for future clinical use.

关键词： gastric cancer BCL2L11 miR-24,tumorigenesis cell apoptosis proliferation migration

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