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Unformatted text preview: members of the Rho subfamily (e.g. RhoA, Rac1 and cdc42). This hierarchical networking between different RAS isoforms is controlled, in part, by interactions with GEFs, GAPs and downstream effectors. For instance, RalGEFs are important in RASmediated transformation. RalGEFs, such as RalGDS, link RAS signaling to the activation of the small GTPases RalA and RalB. In human cells, the RAS effector loop mutant that preferentially activates RalGDS was able to transform cells (23) (Figure 2). Other effectors of RAS signaling pathway Other potential effectors are AF-6, protein kinase C-zeta (PKC-zeta), and Nore1. RAS may use the AF-6 effector to modulate intercellular binding and communication. PKC-zeta displays homology with RAF. A recent study suggests that PKC zeta can activate the RAS pathway independently of RAS (24). Recently, members of the RASSF (RAS association domain family protein) gene family that potentially act as tumor suppressors have been identified as candidate RAS effectors. Loss of expression of Nore1 (novel RAS effector 1) and RASSF1, members of the RASSF gene family, has been observed in a variety of cancers (25). The interaction of RAS with Nore1 has been shown to regulate apoptosis (26) (Figure 2). Figure 4 . The INK4 A/ ARF locus is located on human chromosome 9p21. The two products o f the INK4 A/ ARF locus encode p16INK4A and p14ARF (p19ARF in mice). p16INK4A indirectly regulates RB function and p 14ARF indirectly stabilizes p53. 12 RB and p53 pathways The mammalian INK4A-ARF locus uniquely encodes two distinct proteins, p14ARF and p16INK4A, which both function in cell cycle control and tumor suppression, and are involved in two separate pathways: p16INK4-RB and p14ARF-p53, respectively (Figure 4). These two gene products are transcriptionally initiated from separate promoters and read in two different reading frames: p16INK4A, referred to as INK4A, and p14ARF, referred to as ARF. INK4A positively regulates the RB tumor suppressor by inhibiting CDK4, while wildtype ARF protein forms a complex with HDM2 and p53 and blocks nuclear export of both p53 and HDM2, leading to p53 stabilization and activation in nucleus (27) Figure 5. Figure 5 . Th...
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This document was uploaded on 03/06/2014.

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