Phospho-δNp63α/SREBF1 protein interactions: Bridging cell metabolism and cisplatin chemoresistance

Yiping Huang, Lauren N. Bell, Jun Okamura, Myoung Soo Kim, Robert P. Mohney, Rafael Guerrero-Preston, Edward A. Ratovitski

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3810-3827
Number of pages18
JournalCell Cycle
Volume11
Issue number20
DOIs
StatePublished - Oct 15 2012

    Fingerprint

Keywords

  • Cisplatin
  • Metabolomics
  • Protein interactions
  • Squamous cell carcinomas
  • p53
  • p63

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology
  • Cell Biology

Cite this

Huang, Y., Bell, L. N., Okamura, J., Kim, M. S., Mohney, R. P., Guerrero-Preston, R., & Ratovitski, E. A. (2012). Phospho-δNp63α/SREBF1 protein interactions: Bridging cell metabolism and cisplatin chemoresistance. Cell Cycle, 11(20), 3810-3827. https://doi.org/10.4161/cc.22022