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,
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).