p53-induced apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against neoplastic transformation. It is mediated by upregulation of several proapoptotic genes, including BAX and PUMA (discussed later).
To summarize, p53 is activated by stresses such as DNA damage and assists in DNA repair by causing G1 arrest and inducing the expression of DNA repair genes. A cell with damaged DNA that cannot be repaired is directed by p53 to either enter senescence or undergo apoptosis (see
Fig. 6.21 ). In view of these activities, p53 has been rightfully called the “guardian of the genome.” With loss of normal p53 function, DNA damage goes unrepaired, mutations become fixed in dividing cells, and the cell turns onto a one-way street leading to malignant transformation.
Confirming the importance of TP53 in controlling carcinogenesis, more than 70% of human cancers have a defect in this gene, and the remaining malignant neoplasms often have defects in genes upstream or downstream of TP53. Biallelic abnormalities of the TP53 gene are found in virtually every type of cancer, including carcinomas of the lung, colon, and breast—the three leading causes of cancer deaths. In most cases, mutations affecting both TP53 alleles are acquired in somatic cells. In other tumors, such as certain sarcomas, the TP53 gene is intact but p53 function is lost because of amplification and over-expression of the MDM2 gene, which encodes a potent inhibitor of p53. Less commonly, patients inherit a mutant TP53 allele; the resulting disorder is called the Li-Fraumeni syndrome. As in the case with familial retinoblastoma, inheritance of one mutant TP53 allele predisposes affected http://ebooksmedicine.net
Normal cell Cell with (p53 normal) mutations or loss of p53 p53-dependent genesbinds to DNA
No DNANo cell repair, noTranscription dependent and cycle arrest senescenceindependent effects on targets
Fig. 6.21 The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell cycle arrest in G1 and induction of DNA repair, by transcriptional upregulation of the cyclin-dependent kinase inhibitor CDKN1A (p21) and the GADD45 genes. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53 triggers either apoptosis or senescence. In cells with loss or mutations of TP53, DNA damage does not induce cell cycle arrest or DNA repair, and genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
individuals to develop malignant tumors because only one additional hit is needed to inactivate the second, normal allele. Patients with the Li-Fraumeni syndrome have a 25-fold greater chance of developing a malignant tumor by 50 years of age compared with the general population. In contrast to tumors developing in patients who inherit a mutant RB allele, the spectrum of tumors that develop in patients with the Li-Fraumeni syndrome is much more varied; the most common types are sarcomas, breast cancer, leukemia, brain tumors, and carcinomas of the adrenal cortex. Compared with individuals diagnosed with sporadic tumors, patients with Li-Fraumeni syndrome develop tumors at a younger age and may develop multiple primary tumors.