The miR-17 family links p63 protein to MAPK signaling to promote the onset of human keratinocyte differentiation

PLoS One. 2012;7(9):e45761. doi: 10.1371/journal.pone.0045761. Epub 2012 Sep 24.

Abstract

The p63 protein plays a key role in regulating human keratinocyte proliferation and differentiation. Although some p63-regulating microRNAs (miRNAs) have been identified in the control of epidermal homeostasis, little is known about miRNAs acting downstream of p63. In this paper, we characterized multiple p63-regulated miRNAs (miR-17, miR-20b, miR-30a, miR-106a, miR-143 and miR-455-3p) and elucidated their roles in the onset of keratinocyte differentiation. We identified RB, p21 and multiple MAPKs as targets of these p63-controlled miRNAs. Upon inhibition of most of these miRNAs, we observed defects in commitment to differentiation that could be reversed by siRNA-mediated silencing of their targets. Furthermore, knockdown of MAPK8 and MAPK9 efficiently restored expression of the early differentiation markers keratin 1 and keratin 10 in p63-silenced primary human keratinocytes. These results highlight new mechanistic roles of multiple miRNAs, particularly the miR-17 family (miR-17, miR-20b and miR-106a), as regulatory intermediates for coordinating p63 with MAPK signaling in the commitment of human mature keratinocytes to early differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Differentiation / genetics
  • Antigens, Differentiation / metabolism
  • Cell Differentiation*
  • Cell Line
  • Humans
  • Keratinocytes / metabolism
  • Keratinocytes / physiology*
  • MAP Kinase Signaling System*
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Mitogen-Activated Protein Kinase 9 / genetics
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • RNA Interference*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription Factors / physiology
  • Transcriptome
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • Tumor Suppressor Proteins / physiology

Substances

  • Antigens, Differentiation
  • MIRN143 microRNA, human
  • MIRN17 microRNA, human
  • MicroRNAs
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 8

Grants and funding

Funding provided by CEA (http://dirgre.cea.fr:8000/scripts/home/index.asp) and FRM (http://www.frm.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.