The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP In humans, a common polymorphism involves the substitution of an arginine for a proline at codon position
Abstract The majority of human cancers acquire mutations that abrogate the p53 tumor suppressor network and, as a consequence, p53 is one of the most extensively studied proteins in cancer research. Because of its potent tumor suppressive activity, it is widely assumed that a molecular understanding of p53 action will produce fundamental insights into natural processes that limit tumorigenesis and may identify key molecular targets for therapeutic intervention.
Despite a significant body of literature detailing the biochemical and biological functions of p53, much remains to be elucidated. Indeed, the p53 network is as complex and enigmatic as it is relevant.
It is the goal of this article, written 30 years after the discovery of p53, to present a concise review of the tumor suppressor role of the p53 network and to highlight the context-dependent nature of p53 target-gene functions. Hence, p53 can be activated in response to DNA damage, oncogene activation, or hypoxia, in which it subsequently orchestrates biological outputs such as apoptosis, cell-cycle arrest, senescence, or modulation of autophagy Yee and Vousden ; Riley et al.
Importantly, these p53 tumor suppressor functions are context-dependent and may be influenced by numerous factors, including cell type, microenvironment, and oncogenic events acquired during the course of tumor evolution.
This suggests that, although expression of many genes in the p53 network may be altered in tumors, the critical nodes of the network may differ based on the tumor-cell context. The challenge is to understand which p53 targets or functions are key to the evolution of different tumor types, as this may ultimately identify activities for tumor maintenance and suggest targets for therapeutic intervention.
The amino-terminal phosphorylation of p53 prevents Mdm2 binding, resulting in the stabilization of p Following its stabilization, p53 binds DNA in a sequence-specific manner el-Deiry et al. This finding underscores the importance of p53 binding to DNA in a sequence-specific manner.
However, the simple model of stress-induced, sequence-specific DNA binding is challenged by the recent findings that a significant portion of p53 is bound to DNA in unstressed cells via the carboxy-terminal domain Liu et al.
One rationale for the ubiquitous DNA binding activity of the carboxy-terminal domain of p53 is to facilitate DNA binding and the search for p53 target sites following cellular stress. In addition, studies suggest that basal p53 levels are critical for the assembly of the preinitiation complex on the p21 promoter in unstressed cells Espinosa et al.
Taken together, these studies support the idea that p53 can control gene expression in stressed and unstressed cells. After its stabilization and sequence-specific DNA binding, p53 activates or represses its target genes.
However, such a model under-appreciates the complexity of promoter selection. Promoter selection is dictated by numerous factors, including posttranslational modifications of p53 that can influence the recruitment of p53 binding proteins to specific promoters. A recent review addressing the modes of p53 regulation proposed an under-appreciated step in the physiological activation of p53 Kruse and Gu The authors synthesized the voluminous data on the regulation of p53 and concluded that p53 activation in vivo requires not only its stabilization and activation, but also the release of p53 from an actively repressed state.
This intrinsic potency of p53 is supported by several observations. First, although mdm2 or mdmx aka, mdm4 deficient mice die during embryonic development, this lethality is rescued by codeletion of p53 Montes de Oca Luna et al.
Second, Mdm2 inactivation in cultured cells triggers pmediated apoptosis de Rozieres et al.
Finally, mice harboring a knock-in allele of p53 that is defective in Mdm2 binding p53QSbut retains the ability to bind DNA and transactivate some p53 target genes, die during embryogenesis Johnson et al.
This embryonic lethality may be caused by the inability of mdm2 to interact with and repress the activity of the p53QS mutant. Based on the previous discussion, Kruse and Gu proposed a refined three-step model for promoter-specific activation of p53 activation.
The first step is the stress-induced stabilization of p53 that can occur through various mechanisms, many of which function by inhibiting the ability of Mdm2 to ubiquitinate and degrade p This step requires the acetylation of p53 at specific amino-acid residues, and results in the select activation of a subset of p53 target genes.
The third step is the full activation of specific promoters facilitated by the recruitment and interaction of numerous cofactors by p These cofactors can modify p53, histones, or other transcription factors. Still poorly understood are the precise mechanisms whereby p53 targets specific genes involved in apoptosis, senescence, cell-cycle arrest, or autophagy, although this may involve specific combinations of cofactors and posttranslational modifications.
Some of the most important of these are discussed in the following sections. Cell-cycle Checkpoints Cell-cycle checkpoints are important control features that ensure the fidelity of cell division by verifying whether the processes at each phase of the cell cycle have been accurately completed before progression into the next phase.
In response to various cellular stresses, cells may undergo growth arrest at these checkpoints to prevent the propagation of mutations in the DNA. The role of p53 in cellular growth arrest has been extensively studied, and many of the key upstream regulators and downstream effectors of p53 have been described Giono and Manfredi However, the effects are not as drastic as p53 loss, suggesting that other p53 effectors contribute to this process.
Progression of cells from G2 to mitosis is driven by the maturation-promoting factor MPFwhich comprises a complex of cyclin B1 and cdc2. Cellular Senescence Cellular senescence is a permanent form of cell-cycle arrest that was originally described in normal human fibroblasts by Hayflick Hayflick Senescence can be induced by various stressors, including dysfunctional telomeres, nontelomeric DNA damage, excessive mitogenic signaling including those produced by oncogenesand perturbations in chromatin organization.
DNA tumor virus oncoproteins can bypass senescence, and this frequently involves their ability to inactivate pThis important function of the p53 pathway in reproduction provides a plausible explanation for the evolution of p53 as a tumor suppressor gene and the positive selection of some alleles in the p53 gene and its pathway.
p53, also known as TP53 or tumor protein (EC) is a gene that codes for a protein that regulates the cell cycle and hence functions as a tumor suppression.
It is very important for cells in multicellular organisms to suppress cancer. P53 has been described as "the guardian of the genome", referring to its role in conserving stability by preventing genome mutation (Strachan and Read.
Tp53 gene is mutated in over half of tumor cells; the mutation would alter the structure of p53 protein, thus p53 would lose its function partly or completely. The pmutated cells can not die programmatically, and become tumor cells.
p53 gene - The p53 gene codes for a protein pwhich regulates gene repair in cells.
Mutations in this gene are implicated in around 50 percent of cancers. Mutations in this gene are implicated in around 50 percent of cancers. Sep 19, · The p53 database has also helped reveal the link between liver cancer, Hepatitis B, and aflatoxin, a poison produced by a fungus that grows on peanuts and other grains when they are stored without adequate ventilation.
Reisman et al. () identified 2 promoters in the p53 gene. The first is located to bp upstream of the noncoding first exon, and the second, a stronger promoter, is located within the first intron.