Phospho-ΔNp63α/SREBF1 protein interactions: Bridging cell metabolism and cisplatin chemoresistance
Volume 11, Issue 20
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October 15, 2012
Pages 3810 - 3827http://dx.doi.org/10.4161/cc.22022
: P53, cisplatin, metabolomics, p63, protein interactions, squamous cell carcinomas
Authors: Yiping Huang, Lauren N. Bell, Jun Okamura, Myoung Soo Kim, Robert P. Mohney, Rafael Guerrero-Preston and Edward A. Ratovitski View affiliations
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 specific 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 modifications. 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 affect 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.
Received: August 22, 2012; Accepted: August 29, 2012; Published Online: September 5, 2012
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