TY - JOUR
T1 - Phospho-δNp63α/SREBF1 protein interactions
T2 - Bridging cell metabolism and cisplatin chemoresistance
AU - Huang, Yiping
AU - Bell, Lauren N.
AU - Okamura, Jun
AU - Kim, Myoung Soo
AU - Mohney, Robert P.
AU - Guerrero-Preston, Rafael
AU - Ratovitski, Edward A.
N1 - Funding Information:
This work is dedicated to the memory of the late Dr. Marina Nikolayevna Kiprianova (Institute of Experimental Medicine, Academy of Medical Sciences), whose kind friendship and unparalleled dedication to science inspired the senior author for years after her untimely death. This study was supported in part by the Flight Attendant Research Institutions grant (#082469 to E.A.R.), and by National Cancer Institute grants K01-CA164092 and U01-CA84986 (R.G-P).
PY - 2012/10/15
Y1 - 2012/10/15
N2 - Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of δNp63α was shown to have a role in regulating intracellular δNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the AtM-dependent phosphorylation of δNp63α (p-δNp63α), which is critical for the transcriptional regulation of specifc downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p- δNp63α became more cisplatin-resistant. We also found that p-δNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifcations. Here, we showed that p-δNp63α induced ARG1, GApDH, and Cpt2 gene transcription in cisplatin-sensitive SCC cells, while non-p-δNp63α increased a transcription of CAD, G6pD and FASN genes in cisplatin-resistant SCC cells. We report that the p-δNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby afect tumor cell response to cisplatin-induced cell death, suggesting that the AtM-dependent δNp63α pathway plays a role in the resistance of tumor cells to platinum therapy.
AB - Tumor protein (TP)-p53 family members (TP63, TP63 and TP73) are guardians of the genome and key players in orchestrating the cellular response to cisplatin treatment. Cisplatin-induced phosphorylation of δNp63α was shown to have a role in regulating intracellular δNp63α protein levels. We previously found that squamous cell carcinoma (SCC) cells exposed to cisplatin displayed the AtM-dependent phosphorylation of δNp63α (p-δNp63α), which is critical for the transcriptional regulation of specifc downstream mRNAs and microRNAs and is likely to underlie the chemoresistance of SCC cells. However, SCC cells expressing non-p- δNp63α became more cisplatin-resistant. We also found that p-δNp63α forms complexes with a number of proteins involved in cell death response through regulation of cell cycle arrest, apoptosis, autophagy, RNA splicing and chromatin modifcations. Here, we showed that p-δNp63α induced ARG1, GApDH, and Cpt2 gene transcription in cisplatin-sensitive SCC cells, while non-p-δNp63α increased a transcription of CAD, G6pD and FASN genes in cisplatin-resistant SCC cells. We report that the p-δNp63α-dependent regulatory mechanisms implicated in the modulation of plethora of pathways, including amino acid, carbohydrate, lipid and nucleotide metabolisms, thereby afect tumor cell response to cisplatin-induced cell death, suggesting that the AtM-dependent δNp63α pathway plays a role in the resistance of tumor cells to platinum therapy.
KW - Cisplatin
KW - Metabolomics
KW - Protein interactions
KW - Squamous cell carcinomas
KW - p53
KW - p63
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U2 - 10.4161/cc.22022
DO - 10.4161/cc.22022
M3 - Article
C2 - 22951905
AN - SCOPUS:84868008783
SN - 1538-4101
VL - 11
SP - 3810
EP - 3827
JO - Cell Cycle
JF - Cell Cycle
IS - 20
ER -