NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation

BMC Genomics. 2007 May 31:8:139. doi: 10.1186/1471-2164-8-139.

Abstract

Background: p53 is recognized as a critical regulator of the cell cycle and apoptosis. Mounting evidence also suggests a role for p53 in differentiation of cells including neuronal precursors. We studied the transcriptional role of p53 during nerve growth factor-induced differentiation of the PC12 line into neuron-like cells. We hypothesized that p53 contributed to PC12 differentiation through the regulation of gene targets distinct from its known transcriptional targets for apoptosis or DNA repair.

Results: Using a genome-wide chromatin immunoprecipitation cloning technique, we identified and validated 14 novel p53-regulated genes following NGF treatment. The data show p53 protein was transcriptionally activated and contributed to NGF-mediated neurite outgrowth during differentiation of PC12 cells. Furthermore, we describe stimulus-specific regulation of a subset of these target genes by p53. The most salient differentiation-relevant target genes included wnt7b involved in dendritic extension and the tfcp2l4/grhl3 grainyhead homolog implicated in ectodermal development. Additional targets included brk, sdk2, sesn3, txnl2, dusp5, pon3, lect1, pkcbpb15 and other genes.

Conclusion: Within the PC12 neuronal context, putative p53-occupied genomic loci spanned the entire Rattus norvegicus genome upon NGF treatment. We conclude that receptor-mediated p53 transcriptional activity is involved in PC12 differentiation and may suggest a contributory role for p53 in neuronal development.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Cell Differentiation / drug effects*
  • Chromatin Immunoprecipitation
  • Cloning, Molecular
  • Gene Expression Regulation / drug effects
  • Models, Biological
  • Molecular Sequence Data
  • Nerve Growth Factor / pharmacology*
  • Neurons / cytology*
  • Neurons / drug effects*
  • Neurons / metabolism*
  • PC12 Cells
  • Rats
  • Transcription, Genetic / drug effects*
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Tumor Suppressor Protein p53 / physiology

Substances

  • Tumor Suppressor Protein p53
  • Nerve Growth Factor