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

Normal human fibroblasts have been shown to undergo a p16(Ink4a)-associated senescence-like growth arrest in response to sustained activation of the R as/Raf/ MEK/ERK pathway. We noted a similar p16(Ink4a) associated, senescen ce-like arrest in normal human astrocytes in response to expression of a co nditional form of Raf-1. While HPV16 E7-mediated functional inactivation of the p16(Ink4a)/pRb pathway in astrocytes blocked the p16(Ink4a)-associated growth arrest in response to activation of Raf-1, it also revealed a secon d p21(Cip1)-associated, senescence-associated, beta -galactosidase-independ ent growth arrest pathway. Importantly, the p21(Cip1)-associated pathway wa s present not only in normal astrocytes but also in p53-, p14(ARF)-, and p1 6(Ink4a)/ pRb-deficient high grade glioma cells that lacked the p16(Ink4a)- dependent arrest mechanism. These results suggest that normal human cells h ave redundant arrest pathways, which can be activated by Raf-1, and that ev en tumors that have dismantled p16(Ink4a) dependent growth arrest pathways are potentially regulated by a second p21(Cip1)-dependent growth arrest pat hway.