Proto-oncogenes
المؤلف:
Mary Louise Turgeon
المصدر:
Immunology & Serology in Laboratory Medicine
الجزء والصفحة:
5th E, P479
2025-11-09
103
Proto-oncogenes act as central regulators of the growth in normal cells that code for proteins involved in growth and repair processes in the body. Proteins such as growth factors or transcription factors are necessary for normal growth.
Genetic mutations in proto-oncogenes produce oncogenes. Oncogene activation causes the overexpression of growth- promoting proteins, resulting in hypercellular proliferation and tumorigenesis. Tumor suppressor genes normally counteract proto-oncogenes by encoding proteins that prevent cellular differentiation. When mutations in tumor suppressor genes cause loss of function, the expressed tumor suppressor proteins are no longer able to suppress cellular growth.
For example, the activation of proto-oncogenes (e.g., ras) involved in the growth process or inactivation of suppressor genes (e.g., p53), which keeps growth in check by binding and activating genes that put the brakes on cell division, is responsible for neoplastic transformation of a cell. Defects in the gene for p53 cause about 50% of all cancers.
p53 Protein
The p53 gene (tumor suppressor gene) is located on chromo some 17 and produces a protein that downregulates the cell cycle. A mutation of p53 is associated with an increased incidence of many types of cancer. The p53 tumor suppressor protein is dysfunctional in most human cancers. Even when p53 is not itself mutant, its regulators (e.g., p14ARF, a p53-stabilizing protein) are often altered. The p53 protein is a key responder to various stresses, including DNA damage, hypoxia, and cell cycle aberrations. Specific molecular pathways that activate p53 depend on the nature of the stress and the cell type. Consequently, these determine the specific downstream effectors and cellular response—apoptosis, growth arrest, or senescence.
It is widely believed that the central role of p53 in tumor suppression is to mediate the response to DNA damage. If p53 is missing when damage occurs, cells do not undergo p53 mediated arrest or apoptosis. Cells that have sustained mutations in oncogenes or tumor suppressor genes because of the damage obtain a growth advantage that fuels the development of cancer.
Apparently, DNA damage itself is not the critical event that leads to cancer, as long as the oncogenic stress pathways that activate p53 are intact. For any given cancer type, p53 dysfunction generally correlates with poor treatment response and poor prognosis; therefore, restoration of p53 function is a potential avenue for therapeutic development. Drugs currently being developed will enhance the function of kinases that activate p53 in response to DNA damage.
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