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The role of arf in melanocyte transformation was

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Unformatted text preview: in melanocyte transformation was further characterized in this model. The results showed that in concert with mutant NRAS, the loss of ARF, but not p53 alone, allowed melanocytes to form tumors readily in vivo (85). 20 RAS and cell cycle regulation Oncogenic RAS often deregulates the S-phase entry, and therefore cellular RAS is likely to function as part of the cell cycle control. The role of RAS in cell proliferation and cell cycle control is highlighted by several findings. RAS is activated by serum and various growth factors, and its expression in quiescent immortal mouse fibroblasts leads to cell cycle entry and transformation (86). Treatment of quiescent cells with neutralizing RAS-antibody, in contrast, prevents S-phase entry by serum (87). Besides the growth factor-induced RAS activation, RAS becomes activated independently of extracellular signals in mid-G1-phase, demonstrating the involvement of RAS activity at multiple steps during the G1-phase and S-transition. These results suggest an important role for RAS in cell cycle entry (24). The exact mechanisms of RAS-action in cell cycle regulation are largely unknown. However, cyclin D1, a regulatory subunit of several CDKs, was shown to be upregulated in RAS-transformed cells, leading to an increased proliferation rate or shortened G1phase of the cells (88). These effects are reversed by cyclin D1 antisense oligonucleotides. RAS activates CCND1 (encoding cyclin D1) transcription, and dominant negative RAS prevents serum induction of cyclin D1 protein (89). RASeffectors including RAF and MEK have also been shown to increase cyclin D1 expression. Probable mediators of cyclin D1 induction by RAS are AP-1-complexes composed of Jun and Fos transcription factors. Their levels and activities are regulated by RAS and deletion of AP-1 sequences in the CCND1 promoter abolishes induction by RAS (90). It has been shown that activated ERK causes enhanced expression of immediate early genes, including the AP-1 protein family. Subsequently, dela...
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