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Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function.
Zhang, Mi; Shui, Xindong; Zheng, Xiaoqing; Lee, Jong Eun; Mei, Yingxue; Li, Ruomeng; Tian, Yuan; Zheng, Xiuzhi; Wang, Quling; Wang, Long; Chen, Dongmei; Zhang, Tao; Kim, Byeong Mo; Kim, Jungho; Lee, Tae Ho.
Afiliación
  • Zhang M; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Shui X; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Zheng X; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Lee JE; Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Republic of Korea.
  • Mei Y; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Li R; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Tian Y; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Zheng X; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Wang Q; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Wang L; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Chen D; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Zhang T; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China.
  • Kim BM; Research Center for New Drug Development, AgingTarget Inc., Uiwang-si, Republic of Korea.
  • Kim J; Laboratory of Molecular and Cellular Biology, Department of Life Science, Sogang University, Seoul, Republic of Korea.
  • Lee TH; Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, 1 Xuefu North Road, Fuzhou, 350122, Fujian, China. tlee0813@fjmu.edu.cn.
Arch Pharm Res ; 46(11-12): 882-896, 2023 Dec.
Article en En | MEDLINE | ID: mdl-37804415
ABSTRACT
Breast cancer is one of the major malignancies in women, and most related deaths are due to recurrence, drug resistance, and metastasis. The expression of the mouse double minute 2 (MDM2) oncogene is upregulated in breast cancer; however, its regulatory mechanism has yet to be fully elucidated. Herein, we identified the tumor suppressor death-associated protein kinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2 and phosphorylates it at Thr419. DAPK1-mediated MDM2 phosphorylation promoted its protein degradation via the ubiquitin-proteasome pathway, resulting in upregulated p53 expression. DAPK1 overexpression, but not its kinase activity-deficient form, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown produced the opposite effects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression significantly reduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic effect. Finally, DAPK1 expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest that DAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function in breast cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteína p53 Supresora de Tumor Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Arch Pharm Res Año: 2023 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Proteína p53 Supresora de Tumor Tipo de estudio: Risk_factors_studies Límite: Animals / Female / Humans Idioma: En Revista: Arch Pharm Res Año: 2023 Tipo del documento: Article País de afiliación: China