Arsenic suppresses cell survival via pirh2-mediated proteasomal degradation of ΔNp63 protein

Wensheng Yan, Xiufang Chen, Yanhong Zhang, Jin Zhang, Yong Sam Jung, Xinbin Chen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Transcription factor p63, a member of the p53 family, shares a high degree of sequence similarity with p53. Because of transcription from two distinct promoters, the p63 gene encodes two isoforms, TAp63 and δNp63. Although Tδp63 acts as a tumor suppressor, δNp63 functions as an oncogene and is often overexpressed in squamous cell carcinomas. Thus, therapeutic agents targeting δNp63 might be used to manage tumors that overexpress δNp63. Here we found that arsenic trioxide, a frontline agent for acute promyelocytic leukemia, inhibits δNp63 but not TAp63 expression in time- and dose-dependent manners. In addition, we found that arsenic trioxide decreases the stability of δNp63 protein via a proteasome-dependent pathway but has little effect on the level of δNp63 transcript. Furthermore, we found that arsenic trioxide activates the Pirh2 promoter and consequently induces Pirh2 expression. Consistent with this, we found that knockdown of Pirh2 inhibits, whereas ectopic expression of Pirh2 enhances, arsenic-induced degradation of δNp63 protein. Importantly, we found that knockdown of δNp63 sensitizes, whereas ectopic expression of δNp63 inhibits, growth suppression induced by arsenic. Together, these data suggest that arsenic degrades δNp63 protein at least in part via Pirh2-dependent proteolysis and that inhibition of δNp63 expression facilitates tumor cells to arsenic-induced death.

Original languageEnglish (US)
Pages (from-to)2907-2913
Number of pages7
JournalJournal of Biological Chemistry
Volume288
Issue number5
DOIs
StatePublished - Feb 1 2013

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Arsenic
Proteolysis
Cell Survival
Cells
Tumors
Degradation
Proteins
Enzyme inhibition
Neoplasms
Acute Promyelocytic Leukemia
Protein Stability
Proteasome Endopeptidase Complex
Transcription
Oncogenes
Squamous Cell Carcinoma
Protein Isoforms
Transcription Factors
Genes
Growth
arsenic trioxide

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Arsenic suppresses cell survival via pirh2-mediated proteasomal degradation of ΔNp63 protein. / Yan, Wensheng; Chen, Xiufang; Zhang, Yanhong; Zhang, Jin; Jung, Yong Sam; Chen, Xinbin.

In: Journal of Biological Chemistry, Vol. 288, No. 5, 01.02.2013, p. 2907-2913.

Research output: Contribution to journalArticle

Yan, Wensheng ; Chen, Xiufang ; Zhang, Yanhong ; Zhang, Jin ; Jung, Yong Sam ; Chen, Xinbin. / Arsenic suppresses cell survival via pirh2-mediated proteasomal degradation of ΔNp63 protein. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 5. pp. 2907-2913.
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