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An Alternative Culture Method to Maintain Genomic Hypomethylation of Mouse Embryonic Stem Cells Using MEK Inhibitor PD0325901 and Vitamin C
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miR-203 represses 'stemness' by repressing DeltaNp63.

A M Lena1, R Shalom-Feuerstein, P Rivetti di Val Cervo

  • 1Biochemistry Laboratory IDI-IRCCS and University of Rome 'Tor Vergata', Department of Experimental Medicine and Biochemical Sciences, Rome, Italy.

Cell Death and Differentiation
|May 17, 2008
PubMed
Summary

MicroRNA-203 (miR-203) regulates p63, a key transcription factor for skin development. This microRNA controls the proliferative potential of epithelial stem cells, impacting skin differentiation and development.

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Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Dermatology

Background:

  • The epidermis, a stratified epithelium, relies on the transcription factor p63 for its development and function as a protective barrier.
  • p63 is crucial for maintaining the proliferative capacity of keratinocyte stem cells in the basal layer of the epidermis.
  • Dysregulation of p63 leads to severe defects in epidermal stratification and keratinocyte survival.

Purpose of the Study:

  • To investigate the role of microRNA-203 (miR-203) in keratinocyte differentiation and epidermal development.
  • To determine the molecular targets and regulatory mechanisms of miR-203 in epithelial stem cells.
  • To elucidate the function of miR-203 in controlling the proliferative potential of p63-dependent epithelial precursors.

Main Methods:

  • In vitro studies using primary keratinocytes and embryonic stem cells.
  • Analysis of miR-203 induction during keratinocyte differentiation.
  • Target validation of p63 3'-UTRs by miR-203 using molecular assays.
  • Overexpression studies of miR-203 in proliferating keratinocytes and embryonic stem cells.

Main Results:

  • miR-203 is induced during keratinocyte differentiation and directly targets the 3'-UTRs of both human and mouse p63.
  • Overexpression of miR-203 in proliferating keratinocytes reduces their clonogenic capacity and does not induce full differentiation.
  • miR-203 is downregulated during embryonic stem cell epithelial commitment, and its overexpression impairs stem cell differentiation.

Conclusions:

  • miR-203 acts as a key regulator of p63 levels, specifically targeting DeltaNp63, thereby controlling the proliferative potential of epithelial precursor cells.
  • miR-203 plays a critical role in both keratinocyte differentiation and broader epithelial development by modulating p63-dependent proliferation.
  • miR-203 also influences cell survival upon genotoxic damage in head and neck squamous cell carcinoma by regulating DeltaNp63.