The Ras-Raf-MAPK pathway regulates diverse physiological processes by transmitting signals from membrane based receptors to various nuclear, cytoplasmic and membrane-bound targets, coordinating a large variety of cellular responses. Function of Raf family kinases has been shown to play a role during organism development, cell cycle regulation, cell proliferation and differentiation, cell survival and apoptosis and many other cellular and physiological processes. Aberrations along the Ras-Raf-MAPK pathway play an integral role in various biological processes concerning human health and disease. Overexpression or activation of the pathway components is a common indicator in proliferative diseases such as cancer and contributes to tumor initiation, progression and metastasis. In this review, we focus on the physiological roles of Raf kinases in normal and disease conditions, specifically cancer, and the current thoughts on Raf regulation.

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The life span of model organisms can be modulated by environmental conditions that influence cellular metabolism, oxidation, or DNA integrity. The yeast nicotinamidase gene pnc1 was identified as a key transcriptional target and mediator of calorie restriction and stress-induced life span extension. PNC1 is thought to exert its effect on yeast life span by modulating cellular nicotinamide and NAD levels, resulting in increased activity of Sir2 family class III histone deacetylases. In Caenorhabditis elegans, knockdown of a pnc1 homolog was shown recently to shorten the worm life span, whereas its overexpression increased survival under conditions of oxidative stress. The function and regulation of nicotinamidases in higher organisms has not been determined. Here, we report the identification and biochemical characterization of the Drosophila nicotinamidase, D-NAAM, and demonstrate that its overexpression significantly increases median and maximal fly life span. The life span extension was reversed in Sir2 mutant flies, suggesting Sir2 dependence. Testing for physiological effectors of D-NAAM in Drosophila S2 cells, we identified oxidative stress as a primary regulator, both at the transcription level and protein activity. In contrast to the yeast model, stress factors such as high osmolarity and heat shock, calorie restriction, or inhibitors of TOR and phosphatidylinositol 3-kinase pathways do not appear to regulate D-NAAM in S2 cells. Interestingly, the expression of D-NAAM in human neuronal cells conferred protection from oxidative stress-induced cell death in a sirtuin-dependent manner. Together, our findings establish a life span extending the ability of nicotinamidase in flies and offer a role for nicotinamide-modulating genes in oxidative stress regulated pathways influencing longevity and neuronal cell survival.Genetic manipulations and environmental conditions have been shown to modulate life span in various experimental model systems (1, 2). The environmental conditions include restricted calorie and nutrient availability that affect cellular metabolism as well as stress conditions such as heat and osmotic shock. Accordingly, the genetic manipulations are documented in stress response proteins and in metabolic proteins such as those along the insulin signaling pathway (2, 3). In the yeast Saccharomyces cerevisiae, several of these experimental alternations have been found to affect the replicative life span. Recent studies identified the pyrazinamidase/nicotinamidase gene pnc1 as a key effector of calorie restriction and mild stress-induced life span extension. These conditions induce increased pnc1 transcription and activity (4 -6). In addition, overexpression of PNC1 was shown to be sufficient for extending the replicative life span of yeast.In yeast, PNC1 functions in the NAD salvage pathway by converting nicotinamide to nicotinic acid (see Fig. 1A) (7-9). Nicotinamide is a component of vitamin B3/niacin and serves as a precursor in NAD biosynthesis (10,11). NAD serves as a coenzyme in reversible red...