期刊
ONCOGENE
卷 19, 期 13, 页码 1698-1709出版社
STOCKTON PRESS
DOI: 10.1038/sj.onc.1203471
关键词
TGF beta 1; keratinocytes; replicative senescence; ras oncogene
Previous studies have shown that TGF beta 1 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 TGF beta 1 dependent G1 growth arrest and senescence. The growth arrest is accompanied by a 15-fold increase in total TGF beta 1 secreted and a fourfold increase in secreted active TGF beta 1. When cultured in the presence of a neutralizing antibody to TGF beta 1, the senescence response is suppressed. Levels of the TGF beta 1 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 TGF beta 1 null and dominant negative T beta RII 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 TGF beta 1 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 TGF beta 1 secretion or response is sufficient to block the senescence program. Since v-ras(Ha) transduced TGF beta 1-/- keratinocytes form squamous cell carcinomas following skin grafting, these results suggest that in mouse keratinocytes, defects in TGF beta 1 signaling accelerate malignant progression by overcoming oncogene induced replicative senescence.
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