Induction of p16ink4a and p19ARF by TGFbeta1 contributes to growth arrest and senescence response in mouse keratinocytes

Mol Carcinog. 2009 Mar;48(3):181-186. doi: 10.1002/mc.20472.

Abstract

TGFbeta1 acts as a potent negative regulator of the cell cycle and tumor suppressor in part through induction of cyclin dependent kinase inhibitors p15(ink4b), p21, and p57. We previously showed that primary mouse epidermal keratinocytes (MEK) expressing a v-ras(Ha) oncogene undergo hyperproliferation followed by growth arrest and senescence that was dependent on TGFbeta1 signaling and associated with increased levels of p16(ink4a) and p19(ARF). Here we show that the induction of both p16(ink4a) and p19(ARF) in v-ras(Ha) expressing keratinocytes is dependent on TGFbeta1 signaling, as TGFbeta1 treatment or Smad3 overexpression induces both p16(ink4a) and p19(ARF) protein and mRNA, while Smad3 depletion or Smad7 overexpression blocks induction. Genetic ablation of the cdkn2a (ink4a/arf) locus reduced sensitivity to TGFbeta1 mediated cell cycle arrest and induction of senescence suggesting that alteration of TGFbeta1 responses may be an additional pathway impacted by the inactivation of cdkn2a locus during tumor development.

Publication types

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

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Animals, Newborn
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation*
  • Cell Transformation, Viral
  • Cellular Senescence / physiology*
  • Cyclin-Dependent Kinase Inhibitor p16 / biosynthesis*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Epidermal Cells
  • Extracellular Matrix Proteins / pharmacology*
  • Genes, ras
  • Keratinocytes / drug effects*
  • Keratinocytes / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction
  • Smad2 Protein / genetics
  • Smad2 Protein / metabolism
  • Smad3 Protein / physiology
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Smad7 Protein / genetics
  • Smad7 Protein / metabolism
  • Transforming Growth Factor beta / pharmacology*

Substances

  • Cdkn2a protein, mouse
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p21
  • Extracellular Matrix Proteins
  • Smad2 Protein
  • Smad2 protein, mouse
  • Smad3 Protein
  • Smad3 protein, mouse
  • Smad4 Protein
  • Smad4 protein, mouse
  • Smad7 Protein
  • Smad7 protein, mouse
  • Transforming Growth Factor beta
  • betaIG-H3 protein