Mutant p53 protein is targeted by arsenic for degradation and plays a role in arsenic-mediated growth suppression

Wensheng Yan, Yanhong Zhang, Jin Zhang, Shou Liu, Seong Jun Cho, Xinbin Chen

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

p53 is frequently mutated in tumor cells, and mutant p53 is often highly expressed due to its increased half-life. Thus, targeting mutant p53 for degradation might be explored as a therapeutic strategy to manage tumors that are addicted to mutant p53 for survival. Arsenic trioxide, a drug for patients with acute promyelocytic leukemia, is found to target and degrade a class of proteins with high levels of cysteine residues and vicinal thiol groups, such as promyelocytic leukemia protein (PML) and PML-retinoic acid receptor α fusion protein. Interestingly, wild type p53 is accumulated in cells treated with arsenic compounds, presumably due to arsenic-induced oxidative stresses. In this study, we found that wild type p53 is induced by arsenic trioxide in tumor cells, consistent with published studies. In contrast, we found that arsenic compounds degrade both endogenous and ectopically expressed mutant p53 in time- and dose-dependent manners. We also found that arsenic trioxide decreases the stability of mutant p53 protein through a proteasomal pathway, and blockage of mutant p53 nuclear export can alleviate the arsenic-induced mutant p53 degradation. Furthermore, we found that knockdown of endogenous mutant p53 sensitizes, whereas ectopic expression of mutant p53 desensitizes, tumor cells to arsenic treatment. Taken together, we found that mutant p53 is a target of arsenic compounds, which provides an insight into exploring arsenic compound-based therapy for tumors harboring a mutant p53.

Original languageEnglish (US)
Pages (from-to)17478-17486
Number of pages9
JournalJournal of Biological Chemistry
Volume286
Issue number20
DOIs
StatePublished - May 20 2011

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Arsenicals
Arsenic
Mutant Proteins
Tumors
Degradation
Growth
Cells
Neoplasms
Proteins
Acute Promyelocytic Leukemia
Retinoic Acid Receptors
Oxidative stress
Cell Nucleus Active Transport
Sulfhydryl Compounds
Cysteine
Half-Life
Oxidative Stress
Fusion reactions
Therapeutics
Survival

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Mutant p53 protein is targeted by arsenic for degradation and plays a role in arsenic-mediated growth suppression. / Yan, Wensheng; Zhang, Yanhong; Zhang, Jin; Liu, Shou; Cho, Seong Jun; Chen, Xinbin.

In: Journal of Biological Chemistry, Vol. 286, No. 20, 20.05.2011, p. 17478-17486.

Research output: Contribution to journalArticle

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