Ras Activation

This web page was produced as an assignment for an undergraduate course at Davidson College.

The Ras protein is activated by converting GDP to GTP. In order to exchange GDP for GTP a guanine-nucleotide-exchange factor (GEF) is required to facilitate the transformation* (Bourne et al., 1991) However, regulating the GEF is a guanine-nucleotide-dissociation inhibitor (GDI) which inhibits the replacement of GDP to GTP in the activation process. In the deactivation period GTP is intrinsically converted to GDP by GTPase activating proteins (GAP), however this process is mediated by GDI as well (Boguski et al., 1993).

Several members in the Ras G protein family have been linked to oncogenesis ( Malumbres et al., 1981). Studies suggest that H-, K-, and N- Ras may be tumorigenic because of the inability to delocalize the GTP. Thus, a signal is continuously relayed to the nucleus thereby causing increased proliferation. Trends have been found linking different Ras genes to different human tumors. For instance, the K-Ras is preferentially activated in the colon and pancreas carcinomas, H-Ras is primarily located in the bladder and kidney carcinomas, and the N-Ras is usually found in myeloid and lymphoid disorders (Bos, 1989).

In the gene-knockout studies of Ras particular residues were eliminated in rats. The residues 5-63, 77-92, 109-123, 139-165, and the carboxyl terminal sequences (Cys 186-A-X-COOH) are required for the function of Ras (Barbalid, M., 1987).

Recent research in rats has found that the drug mirthramycin may selectively bind to and inhibit the increased transcriptional activity associated with the tumorigenic H-Ras. Mirthamycin, binds a specific G-C DNA site and thus selectively inhibits traniscription (Campbell et al., 1994).

*The GEF is also referred to as the the guanine-nucleotide-releasing proteins (GNRP) or the guanine-nucleotide-releasing proteins (GNRP).