Home » Key Scientific Articles » Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization,stability, and function

Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization,stability, and function

Shen J1, Sheng X1, Chang Z2, Wu Q3, Wang S1, Xuan Z4, Li D5, Wu Y6, Shang Y4, Kong X6, Yu L7, Li L6, Ruan K6, Hu H6, Huang Y6, Hui L8, Xie D9, Wang F10,Hu R11.

Cell Rep. 2014 Apr 10;7(1):180-93.

1State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

2Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA and

3University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

4College of Chemistry and Materials, Anhui Normal University, Wuhu, Anhui 241000, China and

5University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

6State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

7Institute of Genetics, Fudan University, Shanghai 200433, China and

 8State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

9Institute of Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China and

10School of Public Health, Zhejiang University, Zhejiang 310027, China and

11State Key Laboratory of Molecular Biology, Chinese Academy of Sciences, 320 Yue-yang Road, Shanghai 200031, China; Cancer Research Center, Shanghai Xu-Hui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: [email protected]

 

Abstract

 

Iron excess is closely associated with tumorigenesis in multiple types of human cancers, with underlying mechanisms yet unclear. Recently, iron deprivation has emerged as a major strategy for chemotherapy, but it exerts tumor suppression only on select human malignancies. Here, we report that the tumor suppressor protein p53 is downregulated during iron excess. Strikingly, the iron polyporphyrin heme binds to p53 protein, interferes withp53-DNA interactions, and triggers both nuclear export and cytosolic degradation of p53. Moreover, in a tumorigenicity assay, iron deprivation suppressed wild-type p53-dependent tumor growth, suggesting that upregulation of wild-type p53 signaling underlies the selective efficacy of iron deprivation. Our findings thus identify a direct link between iron/heme homeostasis and the regulation of p53 signaling, which not only provides mechanistic insights into iron-excess-associated tumorigenesis but may also help predict and improve outcomes in iron-deprivation-based chemotherapy.

Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

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