page_title: P53
section_title: Role in disease
hierarchical_section_title: P53 / Role in disease
caption_attribution_description: English: Very high magnification micrograph of an anaplastic astrocytoma.p53 immunostain. The typical features are present: Marked nuclear atypia. Elongated nuclei (consistent with derivation from an astrocyte ). Mitoses. Fine fibrillary processes (consistent with a glial cell population). Cytoplasmic staining of atypical cells with GFAP. p53 immunohistochemical stain positivity. High proliferative rate based on Ki-67 staining. Related images Low mag. Intermed. mag. High mag. Very high mag. GFAP. Very high mag. Ki-67. High mag.
context_page_description: Tumor protein p53, also known as p53, cellular tumor antigen p53, the Guardian of the Genome, phosphoprotein p53, tumor suppressor p53, antigen NY-CO-13, or transformation-related protein 53, is any isoform of a protein encoded by homologous genes in various organisms, such as TP53 and Trp53. This homolog is crucial in multicellular vertebrates, where it prevents cancer formation, and thus functions as a tumor suppressor. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.
  The name p53 was given in 1979 describing the apparent molecular mass; SDS-PAGE analysis indicates that it is a 53-kilodalton protein. However, the actual mass of the full-length p53 protein based on the sum of masses of the amino acid residues is only 43.7 kDa. This difference is due to the high number of proline residues in the protein, which slow its migration on SDS-PAGE, thus making it appear heavier than it actually is. In addition to the full-length protein, the human TP53 gene encodes at least 15 protein isoforms, ranging in size from 3.5 to 43.7 kDa.
context_section_description: If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li-Fraumeni syndrome.
  The TP53 gene can also be modified by mutagens (chemicals, radiation, or viruses), increasing the likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype.
  Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in the process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis, while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of head and neck squamous cell carcinoma. It delivers a functional copy of the p53 gene using an engineered adenovirus.
  Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by the HPV protein E7, allows for repeated cell division manifested clinically as warts. Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia, which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from the effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome.
  The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation. The degradation of the p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function.
  Suppression of p53 in human breast cancer cells is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13.
  One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML.
caption: A micrograph showing cells with abnormal p53 expression (brown) in a brain tumor. p53 immunostain.
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