Cell proliferation is a highly regulated process in which two classes of genes play crucial roles, proto-oncogenes and tumor suppressor genes. Proto-oncogenes induce cell proliferation, and tumor suppressor genes control the levels of proto-oncogenic expression, or the period of activity of proteins transcribed by proto-oncogenes, thus keeping cell proliferation within normal rates. Since uncontrolled cell proliferation leads to tumor formation, genes that prevent abnormal cell proliferation are termed tumor suppressor genes.
When a tumor suppressor gene is mutated or inactivated, cells become either displastic or malignant. When only one copy or allele of a tumor suppressor gene is mutated, dysplasia, or benign overgrowth, usually occurs, due to a lower level of expression of anti proliferative proteins. When a second mutation occurs in the other allele of the same gene, the onset of cancer triggers. Some examples of tumor suppressor genes that are found mutated or inactivated in both hereditary and sporadic cancers are as follows: RB1 (resulting in hereditary retinoblastoma or osteosarcomas), p53 (resulting in Li-Fraumeni syndrome, breast cancer, brain tumors, and leukemias), p16 (resulting in melanomas and pancreatic cancer), and BRCA1 and BRCA2 (resulting in hereditary breast, ovarian and pancreatic cancers).
Additional functions of tumor suppressor genes are more complex and wider than the short definition given above suggests. There are about 12 gene suppressor genes identified today, whose functions are well studied, revealing the fundamental role these genes play in protecting body tissues against abnormal transformations that can lead to cancer. Some products of such genes (i.e., proteins or enzymes) antagonize directly or indirectly the activity of proto-oncogenes. Such proteins are found in every mature tissue of the body in roughly equivalent levels.
The most-studied tumor suppressor gene is p53, that controls phase G1 of the cell cycle and prevents the transition to phase S until DNA damage is repaired. In the case of irreparable DNA damage, p53 activates programmed cell death, also known as apoptosis.
Some oncogenes (i.e., the mutated counterpart of proto-oncogenes) transcribe proteins that inhibit p53 expression or inactivate p53 proteins. Consequently, the DNA-damaged cell escapes apoptosis and respond to mitotic signals, following to cell division. The resultant daughter cells will inherit such mutations and start a lineage of mutated cell clones that will eventually form a tumor. Inactivation of either a tumor suppressor gene or its proteins is also an important step in the development of tumor resistance against anticancer drugs. Cells that have lost the capacity for apoptosis are known as immortalized cells.
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