ras Proteins as Proto- oncogenes & Oncogenes

The ras protein is a monomeric globular protein known as low molecular weight G – protein of 189 amino acids (21 kD molecular mass ) that is present in all eukaryotic organisms from yeast to human. They are synthesized in the cytosol and are associated with the inner side of the plasma membrane. Their evolutionary conservation suggests that they have essential cellular functions including signal transduction ,actin cytoskeletal regulation, vesicle transport, and nuclear-cytoplasmic transport as well as integrity, cell adhesion, proliferation, differentiation, and apoptosis. Furthermore, the biochemical properties of ras proteins include binding, exchange and hydrolysis of guanine nucleotides GTPase activity. To turn on the signaling pathway, ras protein binds to (GTP) in the cell. To turn the pathway off, ras protein breaks up the GTP molecule. Ras hydrolyzes GTP to GDP quickly, turning itself off, with GTPase-activating proteins (GAPs) ensuring that the amount of active ras within the cell is linked to the amount of receptor at the cell surface. A message is passed from the receptor to ras by guanine nucleotide exchange factors (GEFs) that expels the GDP and allows GTP in the cytoplasm to bind in its place. GTP causes a subtle rearrangement of the protein triggering a cascade of mitogen-activated protein kinases. These kinases ultimately phosphorylate the target delivering the message to its final destination. The level of signal passing through ras depends on the balance between the amounts of ras•GTP and ras•GDP complex present in a cell. However, conversion of ras proto-oncogene into ras oncogene through point mutation/s in the gene can affect the cell and make ras to be continually switched on and thus the message is delivered continuously, giving the cell unchecked permission to proliferate. Mutant ras has been identified in cancers of many different origins, including: pancreas (90%), colon (50%), lung (30%), thyroid (50%), bladder (6%), ovarian (15%), breast, skin, liver, kidney, and some leukemia s. There is some hope for treatment of cancers that show mutations in the ras oncogene. The posttranslational addition of a farnesyl moiety to the ras oncoprotein is essential for its transforming activity. Cell-active inhibitors of the enzyme that catalyzes this reaction, protein farnesyltransferase, have been shown to selectively block ras-dependent transformation of cells in culture and thus are promising candidates for targeting of defective cells with ras oncogenes.