Abstract
Normal human fibroblasts have been shown to undergo a p16(Ink4a)-associated senescence-like growth arrest in response to sustained activation of the Ras/Raf/MEK/ERK pathway. We noted a similar p16(Ink4a)-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 p16(Ink4a)/pRb pathway in astrocytes blocked the p16(Ink4a)-associated growth arrest in response to activation of Raf-1, it also revealed a second p21(Cip1)-associated, senescence-associated, beta-galactosidase-independent growth arrest pathway. Importantly, the p21(Cip1)-associated pathway was present not only in normal astrocytes but also in p53-, p14(ARF)-, and p16(Ink4a)/pRb-deficient high grade glioma cells that lacked the p16(Ink4a)-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 p16(Ink4a)-dependent growth arrest pathways are potentially regulated by a second p21(Cip1)-dependent growth arrest pathway.
Highlights
Cell proliferation is dependent on the appropriate transmission of growth signals from the cell membrane to the cell nucleus
The p21Cip1-associated pathway was present in normal astrocytes and 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
The ability of oncogenic Ras to induce a senescence-like growth arrest in normal human fibroblasts (NHF) appears to be closely linked to activation of Raf but not to other downstream targets of Ras, such as phosphatidylinositol 3-kinase or RalGDS, since only mutant forms of Ras that selectively activate the Raf pathway induced growth arrest comparable with that induced by constitutively expressed oncogenic Ras [17]
Summary
Cell proliferation is dependent on the appropriate transmission of growth signals from the cell membrane to the cell nucleus. 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.
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