Defects in TGFβ signaling overcome senescence of mouse keratinocytes expressing v-ras(Ha)

Ryan Tremain, Melissa Marko, Vijayachandra Kinnimulki, Hikaru Ueno, Erwin Bottinger, Adam Glick

Research output: Contribution to journalArticlepeer-review

90 Scopus citations


Previous studies have shown that TGFβ1 expression is upregulated in mouse keratinocytes infected with a v-ras(Ha) retrovirus, although the functional significance of this has not been clear. Here we show that v-ras(Ha) retrovirus transduced primary mouse keratinocytes undergo hyperproliferation followed by a TCFβ1 dependent G1 growth arrest and senescence. The growth arrest is accompanied by a 15-fold increase in total TGFβ1 secreted and a fourfold increase in secreted active TGFβ1. When cultured in the presence of a neutralizing antibody to TGFβ1, the senescence response is suppressed. Levels of the TGFβ1 target p15(ink4b) increase during senescence as does association of this kinase inhibitor with cyclinD/cdk4 complexes. However, p16(ink4a), p53 and p19(ARF) expression also increase during senescence. Genetic analysis shows that TGFβ1 null and dominant negative TβRII expressing v-ras(Ha) keratinocytes resist the G1 growth arrest and do not senescence. This resistance is associated with low expression of p15(ink4b) and p16(ink4a), constitutive Rb phosphorylation and high levels of cdk4 and cdk2 kinase activity. In contrast, inactivation of TGFβ1 secretion or response does not block the induction of p53 and p19(ARF), but the level of p21(waf1), a p53 target gene, is reduced in cyclin D/cdk4 and cyclin E/cdk2 complexes. Thus, although multiple senescence pathways are activated in response to a ras oncogene, inactivation of TGFβ1 secretion or response is sufficient to block the senescence program. Since v-ras(Ha) transduced TGFβ1-/- keratinocytes form squamous cell carcinomas following skin grafting, these results suggest that in mouse keratinocytes, defects in TGFβ1 signaling accelerate malignant progression by overcoming oncogene induced replicative senescence.

Original languageEnglish (US)
Pages (from-to)1698-1709
Number of pages12
Issue number13
StatePublished - Mar 23 2000

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research


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