Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation.
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Huang Y, Ratovitski EA
Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation.
J Biol Chem. 2010 Dec 31;285(53):41422-31. doi: 10.1074/jbc.M110.158642. Epub 2010 Oct 19.
- PubMed ID
- 20959455 [ View in PubMed]
- Abstract
Head and neck squamous cell carcinoma cells exposed to cisplatin display ATM-dependent phosphorylation of the most predominant TP63 isoform (DeltaNp63alpha), leading to its activation as a transcription factor. Here, we found that the phospho-DeltaNp63alpha protein binds to the genomic promoter of RPN13 through the TP63-responsive element. We further found that the phospho-DeltaNp63alpha protein associates with other transcription factors (DDIT3 (also known as CHOP), NF-Y, and NF-kappaB), activating RPN13 gene transcription. Furthermore, cisplatin-induced and phospho-DeltaNp63alpha-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-DeltaNp63alpha-dependent regulation of NOS2 function in cells upon cisplatin treatment, contributing to the cell death pathway of tumor cells.