Harvey ras oncogene
The Harvey ras oncogene, a critical component in the regulation of cellular responses to growth hormones, is a proto-oncogene that can become permanently activated through mutations, leading to uncontrolled cell proliferation. It is implicated in 20 to 30 percent of human cancers and is not inherited but rather acquired, often due to environmental factors or viral infections. Discovered by Jennifer Harvey in 1964 during research on cancer in rodents, the Harvey ras gene encodes the HRas protein, which plays a significant role in growth signaling and cellular behaviors such as apoptosis.
Three main ras genes (HRAS, KRAS, and NRAS) function similarly across various organisms, underscoring their evolutionary importance. Mutant forms of these genes lead to continuously active proteins that stimulate cell growth even without hormonal triggers, posing a heightened cancer risk. The presence of these oncogenes is linked to poor cancer prognosis, and while research is ongoing, pharmacological approaches to inhibit Ras activity, including the promising compound salirasib, are under investigation. Understanding the mechanisms behind the Harvey ras oncogene has significant implications for cancer detection, treatment, and our comprehension of molecular evolution in multicellular organisms.
Harvey ras oncogene
SIGNIFICANCE: The Harvey ras oncogene codes for a protein regulating cellular response to growth hormones. Mutations causing the proto-oncogene, which is a component of normal cells, to be turned on permanently are present in 20 to 30 percent of human malignancies. Environmental carcinogens and retroviruses can effect the transformation of somatic cells. The condition is not hereditary.
Research History
The Harvey ras, or rat sarcoma, oncogene derives its name from Jennifer Harvey, who discovered and investigated it in 1964 in connection with retroviral-induced cancer in laboratory rodents. When the ras retrovirus invades a cell, it provides a template for DNA that attaches to the host DNA, producing viral particles and also an abnormal host protein, HRas. The abnormal protein disrupts normal cell growth, causing uncontrolled proliferation of virally infected cells. In 1982, a team of Boston-area researchers demonstrated that the same mutant protein was present in human bladder cancer.
Scientists have identified three main ras genes regulating human cell response to growth hormones: HRAS, KRAS (Kirsten ras oncogene), and NRAS (neuroblastoma ras oncogene). For each gene, there are a number of possible mutations involving base-pair substitutions. These create a functional protein that is permanently turned on, stimulating DNA replication and cell division even when the hormonal trigger is absent. The Ras protein family is in turn part of a larger superfamily of more than a hundred proteins with similar structure and various regulatory functions.
The normal or forms of ras genes are termed “proto-oncogenes.” Mutations leading to permanent ras activation are dominant. Since normal, fully functional ras genes are essential to cell growth and differentiation in early embryonic development, mutant forms of ras cannot be inherited and usually appear in adulthood. To the extent that inherited cancer susceptibility involves ras, it is because of defects in the genetics of the triggering hormones.
The human ras genes appear to be common to all mammals and to have the same function in mice as in humans. Structurally similar genes are found in such diverse organisms as fruit flies, brewer’s yeast, and cellular slime molds, where they control different processes. Thus, the research identifying and determining the DNA base-pair sequences of ras genes, determining the structure of the proteins produced, and showing how the protein operates at the molecular level has implications not only for the detection and treatment of human cancer but also for elucidating major evolutionary patterns among multicellular eukaryotes. This gene family is absent in bacteria.
Structure and Function of Ras Proteins
The Ras family consists of small monomeric proteins that act as GTPases, binding and hydrolyzing guanosine triphosphate (GTP) to guanosine diphosphate (GDP). The Ras molecules are incorporated in the cell membrane, where they act as switches. They consist of a G protein core surrounded by loops that act as detectors for specific chemical signals. HRas responds to growth hormones, transmitting a signal that stimulates DNA replication, cell growth, and division. Ras genes also govern apoptosis, the programmed death of cells during differentiation of tissues. Other molecules in this superfamily are responsible for the sense of smell in humans and for the detection of mating pheromones in insects.
Mutations in the G core cause Ras proteins to continuously transmit the signal for cell division in the absence of a hormonal trigger. Such mutations, termed “constitutively active,” occur in response to carcinogens and cause trouble when triggered in tissues consisting of cells that divide rapidly in response to hormonal signals.
Implications for Cancer Detection and Treatment
Misregulation of ras oncogenes, including HRas, is directly tied to the development of certain cancer types. As a result, the presence of one of the ras oncogenes worsens the prognosis in human cancer. Such cancers proliferate rapidly, metastasize readily, and are prone to recur. A pharmacological approach that curtails ras activity is one potential method of inhibiting certain cancer types. A Ras inhibitor known as salirasib (farnesylthiosalicylic acid, or FTS) has been tested in cell culture and shows promise as a chemotherapeutic agent but is not yet employed clinically. Commercial tests are available for evaluating tumor samples for the presence of ras oncogenes, but in the absence of specific therapies, their utility is limited, and they are not routinely employed.
Impact
Research on the HRAS oncogene has provided cell biologists and medical researchers with important insights into how growth is regulated at the molecular level. It has helped scientists understand the evolutionary pathways whereby one chemical reaction (GTP hydrolysis) has become the basis for an enormous array of sensory and regulatory functions. The implications for diagnosis and treatment of human cancer are significant, but most have yet to translate into clinical practice.
Key Terms
- apoptosisprogrammed cell death, a necessary part of differentiation in multicellular organisms
- base pair substitutiona type of mutation involving chemical substitution of one base for another in DNA, resulting in substitution of one amino acid for another during protein synthesis
- oncogenea gene involved in cancer
- sarcomaa type of cancer that arises from mesenchymal cells; less common in humans than carcinomas, which arise from epithelial cells
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