What_Are_the_Consequences_of_Ras_Mutation

Consequences Of Ras Mutation Mutations in the three closely related ras genes, H-ras, K-ras, and N-ras, are among the most common mutations found in human cancer, reaching 50% in some types of tumors, such as colorectal carcinoma. Mutations of the K-Ras gene occur in over 90% of pancreatic carcinomas. The ras pathway is important in the transmission of growth-promoting signals from the cell surface receptors, eventually toward the nucleus where these signals affect the production and regulation of other key proteins Most mutations in genes are expected to cause their inactivation, however, in the Ras genes the opposite happens - they become more active in signaling. This is because of the engineering design of the protein. The ras signal is turned off by a molecular switch, which depends on an enzyme activity. In picturesque terms, the nucleotide GTP (guanidine triphosphate) engages the switch to keep it in the "on" state. A portion of the Ras protein has an enzyme activity (a GTPase) which cleaves the GTP. This turns the switch "off" after the brief "on" period. In reality, the mutations of Ras do indeed inactivate a function, as most mutations are expected to do. The GTPase is inactivated by the mutations. But this now means that GTP continues to engage the switch, and the Ras signaling function is unable to be turned "off Ras mutations involve only certain amino acids, those which interfere with the GTPase function. In pancreatic cancer, mutations are essentially seen only at the twelfth position, (codon or amino acid 12), with rare exceptions seen at codon 13. Most mutations in pancreatic cancer change a glycine at codon 12 to a valine or aspartate. The mutation to serine is quite unusual in pancreatic cancer, a peculiar finding since it is a common mutation in other tumor types which have K-ras mutations. Mutations in K-ras occur early in the development of colon carcinoma. This dominantly acting mutation in ras results in its constitutive activation and the subsequent triggering of its signaling pathway by influencing GTPase activity. It is clear that mutations in ras contribute both to the recurrence of the disease and to decrease survival. It is now known that K-ras mutations occur long before the formation of the actual cancer. They form in the precancerous stages, within lesions termed PIN, or Pancreatic Intraepithelial Neoplasia. These are ducts with clones of early neoplastic cells which have not yet invaded through the duct wall. In reality, these lesions are among the most common neoplasms of humans, occurring in nearly a third of elderly people. They are often unfortunately called "hyperplasia’s", a term which implies the lack of neoplastic character. Indeed, a rough estimate suggests that less than 1% of the lesions ever become invasive, which is to say, become a cancer. Thus, in many respects, they are similar to the adenomas of the colon; nearly a third of people will develop adenomas, yet only a small proportion will progress to colon cancer. There is some hope for treatment of cancers that show mutations in the ras oncogene. The early steps of signal transduction, from receptor to Ras, occur on the inside of the cell membrane. Ras itself is tethered to the membrane through a short isoprenoid group, which is attached to a specific cysteine on the protein soon after it is synthesized. The modification is performed by the enzyme farnesyltransferase. Inhibitors of this enzyme block the maturation of Ras, and thus are promising candidates for targeting of rogue cells with ras oncogenes.