Phospho-?Np63?/microRNA feedback regulation in squamous carcinoma cells upon cisplatin exposure.

ABSTRACT: Our previous reports showed that the cisplatin exposure induced the ATM-dependent phosphorylation of ?Np63a, which is subsequently involved in transcriptional regulation of gene promoters encoding mRNAs and microRNAs in squamous cell carcinoma (SCC) cells upon cisplatin-induced cell death. We showed that phosphorylated (p)-?Np63a plays a role in upregulation of pro-apoptotic proteins, while non-p-?Np63a is implicated in pro-survival signaling. In contrast to non-p-?Np63a, p-?Np63a modulated expression of specific microRNAs in SCC cells exposed to cisplatin. These microRNAs were shown to attenuate the expression of several proteins involved in cell death/survival, suggesting the critical role for p-?Np63a in regulation of tumor cell resistance to cisplatin. Here, we studied the function of ?Np63a in transcriptional activation and repression of the specific microRNA promoters whose expression is affected by cisplatin treatment of SCC cells. We quantitatively studied chromatin-associated proteins bound to tumor protein (TP) p63-responsive element, we found that p-?Np63a along with certain transcription coactivators (e.g., CARM1, KAT2B, TFAP2A, etc.) necessary to induce gene promoters for microRNAs (630 and 885-3p) or with transcription corepressors (e.g., EZH2, CTBP1, HDACs, etc.) needed to repress promoters for microRNAs (181a-5p, 374a-5p and 519a-3p) in SCC cells exposed to cisplatin.

SUBMITTER: Huang Y 

PROVIDER: S-EPMC3594269 | biostudies-other | 2013 Feb

REPOSITORIES: biostudies-other