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

ABSTRACT: Head and neck squamous cell carcinoma cells exposed to cisplatin display ATM-dependent phosphorylation of the most predominant TP63 isoform (?Np63?), leading to its activation as a transcription factor. Here, we found that the phospho-?Np63? protein binds to the genomic promoter of RPN13 through the TP63-responsive element. We further found that the phospho-?Np63? protein associates with other transcription factors (DDIT3 (also known as CHOP), NF-Y, and NF-?B), activating RPN13 gene transcription. Furthermore, cisplatin-induced and phospho-?Np63?-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-?Np63?-dependent regulation of NOS2 function in cells upon cisplatin treatment, contributing to the cell death pathway of tumor cells.

SUBMITTER: Huang Y

PROVIDER: S-EPMC3009868 | biostudies-other | 2010 Dec

REPOSITORIES: biostudies-other

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

Huang Yiping Y Ratovitski Edward A EA

The Journal of biological chemistry 20101019 53

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 transcriptio ...[more]

PMID: 20959455

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