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Prolyl hydroxylase 3 stabilizes the p53 tumor suppressor by inhibiting the p53-MDM2 interaction in a hydroxylase-independent manner

文献类型：期刊论文

作者Xu, Yiming3; Gao, Qiang3; Xue, Yaqian3; Li, Xiuxiu3; Qin, Yanqing3; Xu, Liang2; Li, Chenwei1; Fang, Jing4,5; ,
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2019
卷号294期号:25页码:9949-9958
关键词p53 protein stability mouse double minute 2 homolog (MDM2) cancer stem cells colon cancer prolyl hydroxylase 3
ISSN号1357-2725
DOI10.1074/jbc.RA118.007181
文献子类Article
英文摘要Prolyl hydroxylase 3 (PHD3) has initially been reported to hydroxylase hypoxia-inducible factor (HIF) and mediate HIF degradation. More recent studies have shown that, in addition to HIF, PHD3 has also other substrates. Moreover, pHD3 is believed to act as a tumor suppressor, but the underlying mechanism remains to be elucidated. Here, we demonstrate that PHD3 stabilizes p53 in a hydroxylase-independent manner. We found that PHD3 overexpression increases and PHD3 knockdown decreases p53 levels. Mechanistically, PHD3 bound MDM2 proto-oncogene (MDM2) and prevented MDM2 from interacting with p53, thereby inhibiting MDM2-mediated p53 degradation. Interestingly, we found that PHD3 overexpression could enhance p53 in the presence of the prolyl hydroxylase inhibitor dimethyloxalylglycine, and the prolyl hydroxylase activity-deficient variant PHD3-H196A also inhibited the p53-MDM2 interaction and stabilized p53. Genetic ablation of PHD3 decreased p53 protein levels in mice intestinal epithelial cells, but a genetic knockin of PHD3-H196A did not affect p53 protein levels in vivo. These results suggest that the prolyl hydroxylase activity of PHD3 is dispensable for its ability to stabilize p53. We found that both PHD3 and PHD3-H196A suppress the expression of the stem cell-associated gene NANOG and inhibited the properties of colon cancer stem cells through p53. Our results reveal an additional critical mechanism underlying the regulation of p53 expression and highlight that PHD3 plays a role in the suppression of colon cancer cell stemness in a hydroxylase-independent manner.
学科主题Biochemistry & Molecular Biology
WOS关键词BINDING-SITE ; STEM-CELLS ; IKK-BETA ; HYPOXIA ; PROTEIN ; PHD3 ; NANOG ; APOPTOSIS ; MDM2 ; DIFFERENTIATION
语种英语
WOS记录号WOS:000473277900025
出版者AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
版本出版稿
源URL[http://202.127.25.144/handle/331004/562]  
专题中国科学院上海生命科学研究院营养科学研究所
作者单位1.Shanghai Sunstem Biotechnol, Shanghai 200437, Peoples R China;
2.Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai 200031, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China;
4.Qingdao Univ, Canc Inst, Qingdao 266061, Shandong, Peoples R China,
5.Qingdao Univ, Canc Inst, Affiliated Hosp, Qingdao 266061, Shandong, Peoples R China;
推荐引用方式
GB/T 7714		 Xu, Yiming,Gao, Qiang,Xue, Yaqian,et al. Prolyl hydroxylase 3 stabilizes the p53 tumor suppressor by inhibiting the p53-MDM2 interaction in a hydroxylase-independent manner[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2019,294(25):9949-9958.
APA Xu, Yiming.,Gao, Qiang.,Xue, Yaqian.,Li, Xiuxiu.,Qin, Yanqing.,...&,.(2019).Prolyl hydroxylase 3 stabilizes the p53 tumor suppressor by inhibiting the p53-MDM2 interaction in a hydroxylase-independent manner.JOURNAL OF BIOLOGICAL CHEMISTRY,294(25),9949-9958.
MLA Xu, Yiming,et al."Prolyl hydroxylase 3 stabilizes the p53 tumor suppressor by inhibiting the p53-MDM2 interaction in a hydroxylase-independent manner".JOURNAL OF BIOLOGICAL CHEMISTRY 294.25(2019):9949-9958.

入库方式： OAI收割

来源：上海营养与健康研究所

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