Proto-Oncogenes in Cell Development - Essay Example

Numerous oncogenes have been identified as cancers affecting humans. One of these oncogenes is the Ras oncogene that is a family of related cellular proteins. This oncogene belongs to a protein class referred to as small GTPase involved in cellular signal transduction. The oncogene is also involved in the regulation of diverse behaviors of the cell as part of the larger Ras protein superfamily. Their signaling activity results in the growth and division of cells, which means that over-activity on the oncogene’s part, will ultimately cause cancer (Hanahan & Weinberg 2011, p. 654). In fact, the Ras oncogene is the most common in cancer with over 20% of all human cancers possessing permanent Ras mutations and 90% in some cancers like pancreatic cancer. Therefore, inhibitors of the Ras oncogene have been studied in the search for cancer treatment.

            Ras is a protein that binds guanosine nucleotides and is referred to as G-protein. As with other G-proteins, Ras functions as a binary signaling switch with binding of GTP switching it on, while binding of GDP acts to switch it off. The additional phosphate functional group ensures that the switch regions are configured as a loaded spring at Gly-60 and Thr-35 (Weinberg 2013, p. 115). Therefore, the cycling between inactive GDP and active GTP molecules controls the deactivation and activation of the Ras oncogene. The exchange between these molecules is, in turn, facilitated by GEF and GAP molecules, of which GEF promotes the release of GDP and attachment of GTP to the Ras oncogene. Examples of GEF’s include cdc25 and Son of Sevenless (Bock & Marsh 2010, p. 65).

The GEF protein catalyzes the release of GDP by inserting near the binding sites for Mg+ and the P-loop, thus inhibiting their interaction with P-. Within the P-loop, a lysine group is pulled away from GDP by negative residues, increasing the distance between switch I and guanine, and breaking the contact between GDP and Ras (Bock & Marsh 2010, p. 65). Since there is an abundance of activated GTP molecules in the cell, it predominantly binds to the Ras molecule’s nucleotide-binding site. In this configuration, the oncogene has a heightened affinity for effectors that activate its functionality, including PI3K. With numerous of these effectors possessing a Ras binding domain that binds invariably to one of its switch regions, Ras is, therefore, activated. This leads to increased cell differentiation, proliferation, and migration, as well as decreasing cell adhesion (Bock & Marsh 2010, p. 66). These results in decreased apoptosis deregulated cancers and increased metastasis of cancer.

The inappropriate activation of the Ras oncogene is involved in the occurrence of various cancers, including colon and pancreas adenocarcinomas, myeloid leukemia, and thyroid tumors (Schwab 2013, p. 71). Inappropriate Ras oncogene activation could result from mutations, such as those of the erbB receptor and that of p210BCR-ABL, which are upstream of Ras and will inevitably transduce their signals via Ras if constitutively activated. Pont mutations could also activate the Ras oncogene by ensuring that GAP can no longer stimulate the activity of GTPase, increasing mutant active Ras-GTP half-life. In addition, mutations that prevent hydrolysis of GTP result in constitutively active Ras. Because of its prevalence in cancer, the Ras oncogene can be targeted for therapeutic cancer treatment. For instance, the Reovirus, which reproduces excellently in various lines of cancer cells and especially in those with activated Ras pathways, has been found to replicate in tumor cells with activated Ras pathways and eventually kills them (Schwab 2013, p. 72).