Dual growth arrest pathways in astrocytes and astrocytic tumors in response to Raf-1 activation.

Abstract Normal human fibroblasts have been shown to undergo a p16Ink4a-associated senescence-like growth arrest in response to sustained activation of the Ras/Raf/MEK/ERK pathway. We noted a similar p16Ink4a-associated, senescence-like arrest in normal human astrocytes in response to expression of a conditional form of Raf-1. While HPV16 E7-mediated functional inactivation of the p16Ink4a/pRb pathway in astrocytes blocked the p16Ink4a-associated growth arrest in response to activation of Raf-1, it also revealed a second p21Cip1-associated, senescence-associated, β-galactosidase-independent growth arrest pathway. Importantly, the p21Cip1-associated pathway was present not only in normal astrocytes but also in p53-, p14ARF-, and p16Ink4a/pRb-deficient high grade glioma cells that lacked the p16Ink4a-dependent arrest mechanism. These results suggest that normal human cells have redundant arrest pathways, which can be activated by Raf-1, and that even tumors that have dismantled p16Ink4a-dependent growth arrest pathways are potentially regulated by a second p21Cip1-dependent growth arrest pathway.