TY - JOUR
T1 - Phosphorylated TP63 induces transcription of RPN13, leading to NOS2 protein degradation
AU - Huang, Yiping
AU - Ratovitski, Edward A.
PY - 2010/12/31
Y1 - 2010/12/31
N2 - 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.
AB - 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.
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U2 - 10.1074/jbc.M110.158642
DO - 10.1074/jbc.M110.158642
M3 - Article
C2 - 20959455
AN - SCOPUS:78650637919
VL - 285
SP - 41422
EP - 41431
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 53
ER -