Mi Zhang, Xindong Shui, Xiaoqing Zheng, Jong Eun Lee, Yingxue Mei, Ruomeng Li, Yuan Tian, Xiuzhi Zheng, Quling Wang, Long Wang, Dongmei Chen, Tao Zhang, Byeong Mo Kim, Jungho Kim, Tae Ho Lee
Archives of pharmacal research 2023 DecBreast 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. © 2023. The Pharmaceutical Society of Korea.
Mi Zhang, Xindong Shui, Xiaoqing Zheng, Jong Eun Lee, Yingxue Mei, Ruomeng Li, Yuan Tian, Xiuzhi Zheng, Quling Wang, Long Wang, Dongmei Chen, Tao Zhang, Byeong Mo Kim, Jungho Kim, Tae Ho Lee. Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function. Archives of pharmacal research. 2023 Dec;46(11-12):882-896
PMID: 37804415
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