p53

• OMIM: 191170
• UniProt: P04637
• MGI: 98834

The p53 protein is measurable in many types of malignant cells in an increased amount. It is also available in normally growing cells, but can be found in resting cells hardly or not at all. In many tumor types, the gene encoding p53 is mutated. In some, but not all tumors, the protein appears to act as a tumor suppressor. p53 plays a role in the regulation of the cell cycle, where it slows down the activity of a number of genes. p53 is found in all vertebrates.

P53 was discovered by Albert B. DeLeo each other, David P. Lane and Arnold Levine independent in 1979. The human tumor suppressor p53 as a transcription factor regulated by DNA damage, the expression of genes that are involved in the control of the cell cycle, in the induction of apoptosis (programmed cell death ), or involved in the DNA repair. Because of this property is referred to in the literature as " guardian of the genome " p53. The special medical significance is explained by the finding that p53 is mutated in 50 % of all human tumors. The loss of p53 function plays a critical role in the development of cancer, but is not the causal trigger. p53 was chosen because of its importance in 1993 " Molecule of the Year ".

Functions of p53

P53 was given its name due to the apparent molecular mass of 53 kDa on an SDS -PAGE gel. The corresponding gene TP53 tumor suppressor gene located on chromosome 17p13.1. In order to distinguish it from the protein, it is written in italics ( TP53 was once a synonym for human p53 ). The p53 protein is unstable by nature, but is " modeled " at regular intervals. If there is any DNA, however, cause damage, such as a double-strand break, which would be run a replication or mitosis faulty, p53 is stabilized post-translationally within 30 minutes, inducing p53 accumulates in the cell.

The accumulation of p53 has many consequences. On the one hand DNA repair mechanisms are set into motion, the other part of the cell cycle is stopped. The latter is done in that p53 as a transcription factor induced production of the protein p21. p21, in turn, inhibits both the cyclin and the cyclin D/CDK4/6-Komplex E/CDK2-Komplex. These are actually required to release a bound on the protein pRB another transcription factor ( E2F ), which would continue the cell cycle. Thus, the cell gets through p53 time to repair itself before it divides. If the DNA back in order, the p53 levels decrease again, p21 is no longer transcribed and after a while the cell cycle continues.

If p53 however piled high and there are further factors, activated p53 genes of the Bcl2 family (especially the apoptosis regulator BAX), which in turn trigger in the form of a signal cascade of caspases, thus leading to apoptosis (programmed cell death). Accordingly, p53 as a kind of brake which is needed to prevent from uncontrolled cell growth, and other damage, and the mutation results in increased cell division.

Another function of p53 is that it is obviously the human pregnancy hormone hCG controls how scientists were able to prove the University of Leipzig.

Damage of p53

P53 is a key protein of huge importance. A defect has therefore great is harmful. According to current knowledge, there are generally point mutations that lead to a loss of function. As a result of this loss is neither a cell cycle arrest for DNA repair or the induction of apoptosis is possible. The cells begin to divide uncontrollably also with damage in the DNA, it comes to tumor formation.

The following is a list of diseases that are attributable wholly or mainly to mutations in TP53 ( p53 gene).

In glioblastoma multiforme, WHO ° IV, the p53 gene is also mutated: the primary GBM <30 %, the secondary ( due to progression of low grade glioma, such as the diffuse astrocytoma WHO ° II or anaplastic astrocytoma WHO ° III) GBM > 65% as well as the giant cell glioblastoma 30 to 40 %.

Patients who are born with the Li -Fraumeni syndrome have a congenital mutation in TP53. So it is in people with this mutation in the earliest childhood to various tumors, such as breast cancer, leukemia, brain tumors, and more. Cause cancer, however, is probably not the mutation of TP53 itself, but the high rate of cell division during the embryonic growth, in spite of defects in the DNA, so that damage accumulate and further genes could be damaged for the regulation of cell growth. How Heidelberg researchers described in 2012 in the journal Cell, have tumors in patients with congenital TP53 mutations beyond heaped characteristics of catastrophic chromosome rearrangements ( chromothripsis ). TP53 mutations could either be the cause of this massive DNA damage, or prevent cell death by apoptosis, despite massive destruction of the chromosome structure. Since each x-ray or chemotherapy increases the mutation rate, both the diagnosis and the treatment of patients with Li -Fraumeni syndrome is particularly difficult.

In addition to spontaneously occurring mutations there are also other causes of damage to p53 or its functions. So there are tumor-inducing viruses ( so-called oncoviruses ), inhibit, degrade or accelerate the natural decomposition of the p53. This strategy is to use the virus as well as viral diseases can trigger apoptosis and thus the virus would prevent their proliferation.

Furthermore, p53 can be damaged by chemical substances, for example, by the contained in tobacco smoke, benzo [a ] pyrene or aflatoxin. These substances leave characteristic features in the damaged DNA and can be identified as the cause.

Relationship between p53 and life expectancy

Experiments on fruit flies suggest that an artificially reduced activity of the anti-tumor protein positive in the test animals to the lifetime effect. The protein behaves as normal, however, active ( on active ), the treated mice age much more quickly than usual. However, the mechanism itself has not yet been explained.