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.
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Cancer Research