p53 is an apoptosis promoter protein that acts as a sensor of cellular stress in response to hyperproliferative signals, DNA damage, hypoxia, telomere shortening, and others.
Its gene was initially described as an oncogene, related to different types of cancer. It is now known that it has tumor suppression ability, but that it is also essential for cell survival, including cancer cells.
Structure of the p53 protein (Source: Protein Data Bank. David Goodsell. Via Wikimedia Commons)
It has the ability to stop the cell cycle, allowing the cell to adjust and survive pathological damage, or in the case of irreversible damage, it can trigger cell suicide by apoptosis or "senescence" that stops cell division.
The p53 protein can regulate a variety of cellular processes in a positive or negative way, maintaining homeostasis under standard conditions.
Listed as a transcription factor, p53 acts by regulating the transcription of the gene encoding the cyclin-dependent kinase p21, responsible for regulating entry into the cell cycle.
Under normal conditions, cells have a low level of p53, since this, before being activated, is interacting with the MDM2 protein, which acts as ubiquitin ligase, marking it for degradation in proteasomes.
Generally, the stress caused by DNA damage causes an increase in p53 phosphorylation, which reduces the binding of the MDM2 protein. This leads to an increase in the concentration of p53, which allows it to act as a transcriptional factor.
P53 binds to DNA to exert its function as a transcriptional factor, inhibiting or promoting the transcription of genes. All DNA sites to which the protein binds are located in the 5 'region of the consensus sequences.
Structure
The structure of the p53 protein can be divided into 3 regions:
(1) An amino terminus, which has the transcriptional activation region; 4 of the 6 known phosphorylation sites for protein regulation are located there.
(2) A central region, which contains blocks of highly conserved sequences where most of the oncogenic mutations are located.
This region is necessary for the specific binding of p53 to DNA sequences, and it has been observed that there are also binding sites for metal ions, which appear to maintain the conformational arrangements of the protein.
(3) A carboxyl terminus, which contains the oligomerization and nuclear localization sequences; two other phosphorylation sites are located at this end. This region has been described by scientists as the most complex of p53.
The carboxyl terminus of p53 contains a region that negatively regulates the specific binding capacity of p53 to DNA.
Within the p53 protein there are five domains that are conserved from amphibians to primates; one located at the amino terminal end and the other four within the central region.
Features
Two possible functions have been identified for the p53 protein; the first in promoting cell differentiation and the second as a genetic control point for the arrest of the cell cycle in response to the damage caused to DNA.
The p53 protein induces in B lymphocytes the differentiation from early to advanced stages, it participates in the arrangement of the major histocompatibility complex.
p53 is found at high levels in testicular seminiferous tubules, particularly in those cells in the pachytene stage of meiosis, at which point cell transcription stops.
In the oocytes and early embryos of Xenopus Iaevis there are also high concentrations of the protein p53, which suggests that it could play a crucial role in the early development of embryos.
Experiments carried out with genetically modified mice, for which the p53 protein gene was deleted, indicate that its expression is not essential for the early stages of embryogenesis, but it does have an important role in murine development.
P53 is activated by DNA damage caused by high irradiation with UV light, ionizing radiation, by mitomycin C, etoposide, by the introduction of DNA restriction enzymes into cell nuclei, and even by in situ DNA transfection.
Cellular cycle
If DNA damage is not repaired before replicative synthesis or mitosis, spread of mutagenic lesions could occur. p53 plays a fundamental role as a damage detector in the genome and guardian of the G1 phase in the cell cycle.
The p53 protein controls the advancement of the cell cycle mainly by activating 3 genes: AT, p53 and GADD45. These are part of a signal transduction pathway that causes cell cycle arrest after DNA damage.
The p53 protein also stimulates the transcription of the p21 gene, which binds to the G1 / S-Cdk, E / CDK2, S-Cdk, and cyclin D complexes and inhibits their activities, resulting in hypophosphorylation of pRb (retinoblastoma protein) and thus the arrest of the cell cycle.
The p53 protein participates in the induction of p21Waf1 transcription, resulting in cell cycle arrest in G1. It can also contribute to G2 cycle arrest, by inducing transcription of GADD45, p21, 14-3-3 and by repressing cyclin B transcription.
The biochemical pathways involved in the arrest of the G2 phase of the cell cycle are regulated by CdC2, which has four transcriptional targets: p53, GADD45, p21 and 14-3-3.
Entry into mitosis is also regulated by p53, since this protein negatively regulates the expression of the cyclin B1 gene and the Cdc2 gene. The union of both is necessary for entry into mitosis, it is believed that this occurs to ensure that cells do not escape the initial blockage.
Another p53-dependent mechanism is the binding between p21 and the proliferating cell nuclear antigen (PCNA), this being the main complementary subunit of replicative DNA polymerase, which is necessary for DNA synthesis and repair.
Diseases
The p53 protein has been classified as "guardian of the genome", "death star", "good cop, bad cop", "acrobat of tumorigenesis", among others, since it fulfills important functions both in pathologies and in cancer.
Cancer cells are generally disrupted and their survival and proliferation depend on alterations in pathways controlled by p53.
The most common alterations observed in human tumors are in the DNA-binding domain of p53, which disrupt its ability to act as a transcriptional factor.
Molecular and immunohistochemical analyzes of patients with breast cancer have shown an aberrant accumulation of the p53 protein in the cytoplasm of tumor cells, far from its normal location (nucleus), which seems to indicate some type of functional / conformational inactivation of the tumor. protein.
Abnormal accumulation of the p53 protein regulatory MDM2 protein is seen in most tumors, especially sarcomas.
The viral protein E6 expressed by HPV specifically binds to the p53 protein and induces its degradation.
For researchers, the p53 protein remains a paradigm, since most point mutations lead to the synthesis of a stable, but "inactive" protein in the nucleus of tumor cells.
Li-Fraumeni syndrome
As mentioned, the p53 protein plays a crucial role in the development of multiple classes of cancer, and families of patients with Li-Fraumeni syndrome are predisposed to many of them.
Li-Fraumeni syndrome was first described in 1969. It is a hereditary genetic condition whose underlying mechanism has to do with different germline mutations in the p53 gene, which ultimately lead to different types of cancer in humans.
Initially, these mutations were believed to be responsible for bone tumors and soft tissue sarcomas, as well as premenopausal breast carcinoma, brain tumors, neo-cortical carcinomas, and leukemias; all in patients of different ages, from juveniles to adults.
At present, numerous studies have shown that these mutations are also the cause of melanomas, gastric and lung tumors, pancreatic carcinomas, among others.
References
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