Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation.
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.
Huang
Yiping
Y
Department of Dermatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
Ratovitski
Edward A
EA
D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D023081:CCAAT-Binding Factor / Q000378:metabolism*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics; D008969:Molecular Sequence Data; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid; D015534:Trans-Activators / Q000378:metabolism*; D051742:Transcription Factor CHOP / Q000378:metabolism*; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C500781:ADRM1 protein, human; D000970:Antineoplastic Agents; D023081:CCAAT-Binding Factor; C497249:DDIT3 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D034741:RNA, Small Interfering; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D051742:Transcription Factor CHOP; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D002945:Cisplatin