Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation

Yiping Huang, Edward A. Ratovitski

Research output: Contribution to journalArticlepeer-review

Abstract

Head and neck squamous cell carcinoma cells exposed to cisplatin display ATM-dependent phosphorylation of the most predominant TP63 isoform (ΔNp63α), leading to its activation as a transcription factor. Here, we found that the phospho- ΔNp63α protein binds to the genomic promoter of RPN13 through the TP63-responsive element. We further found that the phospho-ΔNp63α protein associates with other transcription factors (DDIT3 (also known as CHOP), NF-Y, and NF- κB), activating RPN13 gene transcription. Furthermore, cisplatin- induced and phospho-ΔNp63α- dependent RPN13 gene transcription leads to NOS2 degradation. Finally, we show that RPN13 knockdown by siRNA essentially rescues NOS2 from cisplatin-dependent inactivation. These data provide a novel mechanism for the phospho- ΔNp63α-dependent regulation of NOS2 function in cells upon cisplatin treatment, contributing to the cell death pathway of tumor cells.

Original languageEnglish (US)
Pages (from-to)41422-41431
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number53
DOIs
StatePublished - Dec 31 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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