|
 
p53 AND HUMAN CANCERSp53 is a nuclear phosphoprotein which acts as a tumor suppressor. The gene for p53 is located on the short arm of chromosome 17 at 17p13.105-p12. The open reading frame of p53 codes for a protein with 393 amino acids (53 kD). The central region of the protein contains the DNA-binding domain. The structure of p53 consists of a large beta-sandwich which encompasses 3 loop-based elements and is composed of 2 anti-parallel beta-sheets encompassing 4 and 5 beta-strands, respectively. The first loop binds to DNA within the major groove and the second loop binds to DNA within the minor groove. The function of the third loop is stabilization of the second loop. p53 functions by binding to p53 DNA recognition sequences and regulates transcription of growth-regulatory genes. Various p53 recognition sequences have recently been identified. pOST2 contained two copies of a palindromic high-affinity DNA-binding sequence for p53 The other p53 recognition sequences included p53-binding regions found in the human ribosomal gene cluster (pRGC) region and in the murine muscle creatine kinase promoter (pMCK). p53 protein is undetectable or is present at a low level in resting cells. On the other hand, it is found in large amounts in a wide variety of transformed cells, and in many actively proliferating, and nontransformed cells. The function of this protein is poorly understood. However, it is thought that it may be implicated in the regulation of the cell cycle. Mitogens induce the synthesis of p53. On the other hand, microinjection of p53 specific-antibody blocks the entry of cells into the S-phase. In the June 1, 1996 issue of The Journal of Immunology, Boehme et al described that T cell blasts derived from mice containing a germ-line deficiency of the p53 tumor suppressor gene were susceptible to TCR-induced apoptosis to the same degree as the wild-type T cells. These results suggested that in the in mature T cells, TCR-mediated apoptosis, takes place via a p53 independent pathway. Gene knockout studies have revealed that a subset of p53-deficient embryos exhibit exencephaly. In addition, mice homozygous for the null allele appear normal but are prone to the spontaneous development of a variety of neoplasms by 6 months of age. Neoplasms can be induced by the inactivation of p53 by mutation, or by virtue of interaction with oncogene products of DNA tumor viruses. Therefore, p53 is considered to be a tumor suppressor. In addition, human cancers are associated with mutations in the p53 gene. The mutations that inactivate p53 are localized in highly conserved protein domains which affect residues 175, 248, and 273. The residues, most frequently mutated in cancers, all reside at or near the protein-DNA interface and majority of the missense mutations are located in 1 of the 3 DNA loops. Mutations of the p53 gene have been demonstrated in tumors of the colon, breast, lung, ovary, bladder, and many other organs. References: Database Links:
Gene Map Locus: 17p13.1 |
 |
![[OMIM]](../../images/omim.gif)
