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KMID : 0043320230460110882
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Archives of Pharmacal Research
2023 Volume.46 No. 11 p.882 ~ p.896
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Death-associated protein kinase 1 phosphorylates MDM2 and inhibits its protein stability and function
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Mi Zhang
Xindong Shui
Xiaoqing Zheng
Lee Jong-Eun
Yingxue Mei
Ruomeng Li
Yuan Tian
Xiuzhi Zheng
Quling Wang
Long Wang
Dongmei Chen
Tao Zhang
Kim Byeong-Mo
Kim Jung-Ho
Lee Tae-Ho
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Abstract
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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 identifi ed the tumor suppressor death-associated proteinkinase 1 (DAPK1) as a novel MDM2 regulator by unbiased peptide library screening. DAPK1 is directly bound to MDM2and 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-defi cientform, decreased colony formation and increased doxorubicin-induced cell death; however, DAPK1 knockdown producedthe opposite eff ects in human breast cancer cells. In a xenograft tumorigenesis assay, DAPK1 overexpression signifi cantlyreduced tumor formation, whereas inhibition of DAPK1 kinase activity reduced its antitumorigenic eff ect. Finally, DAPK1expression was negatively correlated with MDM2 levels in human breast cancer tissues. Thus, these results suggest thatDAPK1-mediated MDM2 phosphorylation and its protein degradation may contribute to its antitumorigenic function inbreast cancer.
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KEYWORD
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Breast cancer, Death-associated protein kinase 1 (DAPK1), Mouse double minute 2 (MDM2), p53, Tumor suppressor, Tumorigenesis
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