Our laboratory has hypothesized that the ratio of Raf to Myc activity determines the fate of cells in terms of proliferation, differentiation, and apoptosis. It was proposed that overexpression of Raf leads to differentiation, whereas Myc overexpression induces apoptosis. Our recent studies have examined the role of Raf activity in the differentiation. We showed that prolonged high Raf kinase activity is necessary for differentiation of rat pheochromocytoma PC12 cells. These cells form neurite outgrowths when the Raf-1 protein is constitutively activated by specific (for nerve cells the differentiation factor is nerve growth factor) or unspecific (only growth-inducing factors, like epidermal growth factor, tumor growth factor-alpha, and fibroblast growth factor-beta) factors. The latter cause only a transient Raf-1 activation, but in combination with tumor promoter agent phorbol myristate acetate or in cells that overexpress growth factor receptors, they cause a prolonged Raf-1 activation and differentiation.
