Novel aspects of Ras proteins biology: regulation and implications

The importance of Ras proteins as crucial crossroads in cellular signaling pathways has been well established. In spite of the elucidation of the mech anism of RAS activation by growth factors and the delineation of MAP kinase cascades, the overall framework of Ras interactions is far from being comp lete. Novel regulators of Ras GDP/GTP exchange have been identified that ma y mediate the activation of Ras in response to changes in intracellular cal cium and diacylglycerol, The direct activation of Ras by free radicals such as nitric oxide also suggests potential regulation of Ras function by the cellular redox state. In addition, the array of Ras effecters continues to expand, uncovering links between Ras and other cellular signaling pathways. Ras is emerging as a dual regulator of cellular functions, playing either positive or negative roles in the regulation of proliferation and apoptosis , The signals transmitted by Ras may be modulated by other pathways trigger ed in parallel, resulting in the final order for proliferation or apoptosis , The diversity of ras-mediated effects may be related in part to different ial involvement of Ras homologues in distinct cellular processes. The study of Ras posttranslational modifications has yielded a broad battery of inhi bitors that have been envisaged as anti-cancer agents. Although an irrevers ible modification, Ras isoprenylation appears to be modulated by growth fac tors and by the activity of the isoprenoid biosynthetic pathway, which may lead to changes in Ras activity.