Induction of p16ink4a and p19ARF by TGFβ1 contributes to growth arrest and senescence response in mouse keratinocytes

Kinnimulki Vijayachandra, William Higgins, Jessica Lee, Adam Glick

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

TGFβ1 acts as a potent negative regulator of the cell cycle and tumor suppressor in part through induction of cyclin dependent kinase inhibitors p15ink4b, p21, and p57. We previously showed that primary mouse epidermal keratinocytes (MEK) expressing a v-rasHa oncogene undergo hyperproliferation followed by growth arrest and senescence that was dependent on TGFβ1 signaling and associated with increased levels of p16 ink4a and p19ARF. Here we show that the induction of both p16ink4a and p19ARF in v-rasHa expressing keratinocytes is dependent on TGFβ1 signaling, as TGFβ1 treatment or Smad3 overexpression induces both p16ink4a and p19ARF protein and mRNA, while Smad3 depletion or Smad7 overexpression blocks induction. Genetic ablation of the cdkn2a (ink4a/arf) locus reduced sensitivity to TGFβ1 mediated cell cycle arrest and induction of senescence suggesting that alteration of TGFβ1 responses may be an additional pathway impacted by the inactivation of cdkn2a locus during tumor development.

Original languageEnglish (US)
Pages (from-to)181-186
Number of pages6
JournalMolecular Carcinogenesis
Volume48
Issue number3
DOIs
StatePublished - Mar 1 2009

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cancer Research

Fingerprint Dive into the research topics of 'Induction of p16<sup>ink4a</sup> and p19<sup>ARF</sup> by TGFβ1 contributes to growth arrest and senescence response in mouse keratinocytes'. Together they form a unique fingerprint.

  • Cite this