Genetics

Tumor Suppressor Gene P53



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Tumor-suppressor genes are those that encode proteins which inhibit cell proliferation. Loss of one or more of these brakes contributes to the development of many cancers. Five broad classes of proteins are generally recognized as being encoded by tumor-suppressor genes, namely, intracellular proteins, receptors for secreted hormones, checkpoint-control proteins, apoptosis promoting proteins and DNA repair enzymes.

Intracellular proteins, such as p16 cyclin-kinase inhibitor, regulate or inhibit progression through a specific stage of the cell cycle. Receptors for secreted hormones, for example tumor-derived growth factor, function to inhibit cell proliferation. Checkpoint-control proteins are proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal

The p53 gene may be one of the most important tumor-suppressor gene in human cancer because this tumor suppressor gene is mutated in about half of all human cancers. Mutations in the p53 gene allow cancer cells to survive and proliferate despite DNA damage. Its triple involvement in cell-cycle control, apoptosis, and in maintenance of genetic stability-all aspects of the fundamental role of the p53 protein in protecting the organism against cellular damage and disorder. p53 protein exerts its cell-cycle effects, in part at least, by binding to DNA and inducing the transcription of p21,a regulatory gene whose protein product binds to Cdk complexes required for entry into and progress through S-phase. p21 protein prevents the cell from entering S phase and replicating its DNA by blocking the kinase activity of these Cdk complexes.

p53 is not required for normal development in that its function is required only occasionally or in special circumstances. When normal cells are deprived of oxygen or exposed to treatments that damage DNA, such as ultraviolet light or gamma rays, they raise their concentration of p53 protein by reducing the normally rapid rate of degradation of the molecule. In these cases, the high level of p53 protein acts to limit the harm done. Depending on circumstances and severity of damage, p53 may either drive the damaged or mutant cell to commit suicide by apoptosis, a relatively harmless event for the multicellular organism or trigger a mechanism that bars the cell from dividing so long as the damage remains unrepaired. The protection provided by p53 is an important part of the reason why mutations that activate oncogenes such as Ras and Myc are not enough by themselves to create a tumor.

Cells defective in p53 escape apoptosis, if their DNA is damaged by radiation or carry on dividing, plunging into DNA replication without pausing to repair the breaks and other DNA lesions that the damage has caused. The cell either dies or survives and proliferates with a corrupted genome. A common consequence is that chromosomes become fragmented and incorrectly rejoined, creating, through further rounds of cell division, an increasingly disrupted genome. Gene amplification lead to loss of tumor suppressor genes and activation of oncogenes, which may cause the cell to develop resistance to therapeutic drugs.

In short, loss of p53 activity allows faulty mutant cells to continue through the cell cycle, allows them to escape apoptosis and leads to the genetic instability characteristic of cancer cells, allowing further cancer-promoting mutations to accumulate as they divide.

Loss-of-function mutations in tumor-suppressor genes are oncogenic or cancer-causing. Both alleles of a tumor-suppressor gene must be lost or inactivated in order to promote tumor development as generally one copy of a tumor-suppressor gene suffices to control cell proliferation. Tumor-suppressor genes in many cancers have deletions or point mutations that prevent production of any protein or lead to production of a nonfunctional protein. In an example, loss of p16/INK Cdk inhibitor mimics cyclin D over-expression. Also, loss of pRB causes cancer caused in childhood retinoblastoma by forming retinal tumours typically affecting young children. The retinal cells lacking a functional RBgene proliferate out of control. rbnull cells are either homozygous for a single mutant rballele or are heterozygous for two different rbmutations. In homozygous null rbcells, Rb protein is permanently inactive. Rb protein binds to the E2F transcription factor in the hypo-phosphorylated state, preventing E2F from promoting the transcription of genes whose products are needed for S-phase functions such as DNA replication.  Inactive Rb is unable to bind E2, thus E2F can promote the transcription of S-phase genes. The arrest of normal cells in late G1 does not occur in retinoblastoma cells.

Cancer cells tend to be more susceptible than normal cells to the damaging effects of ionizing radiation because they lack an ability to arrest the cell cycle and make the necessary repairs. Unfortunately, the same genetic defects may render some cancer cells resistant to radiation treatment, as they may also be less adept at activating apoptosis in the face of DNA damage.

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