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Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function

Shen, Jia and Sheng, Xiangpeng and Chang, ZeNan and Wu, Qian and Wang, Sheng and Xuan, Zongliang and Li, Dan and Wu, Yalan and Shang, Yongjia and Kong, Xiangtao and Yu, Long and Li, Lin and Ruan, Kangchen and Hu, Hongyu and Huang, Ying and Hui, Lijian and Xie, Dong and Wang, Fudi and Hu, Ronggui (2014) Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function. Cell Reports, 7 (1). pp. 180-193. ISSN 2211-1247. PMCID PMC4219651. http://resolver.caltech.edu/CaltechAUTHORS:20140408-110553348

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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 with p53-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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.celrep.2014.02.042DOIArticle
http://www.cell.com/cell-reports/abstract/S2211-1247%2814%2900156-9PublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219651/PubMed CentralArticle
Additional Information:© 2014 The Authors Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/). Received: August 7, 2013 Revised: December 2, 2013. Accepted: February 27, 2014. Published: March 27, 2014. We gratefully acknowledge Dr. Alexander Varshavsky (California Institute of Technology) for his generous support, encouragement in initiating the project, and advice on manuscript preparation. The authors are particularly thankful to Dr. Bert Vogelstein (Johns Hopkins University) for his critical reading of the manuscript, generous support, and sharing key reagents. The plasmid encoding GST-CRM1/XPO1 was a gift from Dr. Chuanmao Zhang (Peking University). This work was supported by funding from the National Science Foundation of China to R.H. (31270828 and 31070678) and grants from the Ministry of Science and Technology, China (2010CB912101, 2012CB910800, and 2013CB910900 to R.H. and 2011CB915501 to K.R.). R.H. was also supported by a Sanofi-aventis SIBS Young Investigator award and funding from the Cancer Center of Xuhui Central Hospital (CCR2012003), Shanghai Institute of Neurosciences (SKLN-201206), and Shanghai Municipal Department of Science and Technology (PJ[2010] 00123). We are grateful to Drs. Dangsheng Li and Lin Li (SIBCB), Zhenggang Liu (National Cancer Institute), and Douglas Rees (California Institute of Technology) for helpful discussions. We also thank Dr. Yongguang Gao for his help in image processing.
Funders:
Funding AgencyGrant Number
National Natural Science Foundation of China31270828
National Natural Science Foundation of China31070678
Ministry of Science and Technology (China)2010CB912101
Ministry of Science and Technology (China)2012CB910800
Ministry of Science and Technology (China)2013CB910900
Ministry of Science and Technology (China)2011CB915501
Sanofi-AventisUNSPECIFIED
Cancer Center of Xuhui Central HospitalCCR2012003
Shanghai Institute of NeurosciencesSKLN-201206
Shanghai Municipal Department of Science and TechnologyPJ[2010] 00123
National Cancer InstituteUNSPECIFIED
PubMed Central ID:PMC4219651
Record Number:CaltechAUTHORS:20140408-110553348
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20140408-110553348
Official Citation:Jia Shen, Xiangpeng Sheng, ZeNan Chang, Qian Wu, Sheng Wang, Zongliang Xuan, Dan Li, Yalan Wu, Yongjia Shang, Xiangtao Kong, Long Yu, Lin Li, Kangchen Ruan, Hongyu Hu, Ying Huang, Lijian Hui, Dong Xie, Fudi Wang, Ronggui Hu, Iron Metabolism Regulates p53 Signaling through Direct Heme-p53 Interaction and Modulation of p53 Localization, Stability, and Function, Cell Reports, Volume 7, Issue 1, 10 April 2014, Pages 180-193, ISSN 2211-1247, http://dx.doi.org/10.1016/j.celrep.2014.02.042. (http://www.sciencedirect.com/science/article/pii/S2211124714001569)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44762
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:08 Apr 2014 21:00
Last Modified:21 Jul 2017 21:00

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