p53

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P53
P53
Ribbon / surface model of p53 on DNA according to PDB  1TUP

Existing structural data : 1a1u , 1aie , 1c26 , 1gzh , 1hs5 , 1kzy , 1olg , 1olh , 1pes , 1pet , 1sae , 1saf , 1sag , 1sah , 1sai , 1saj , 1sak , 1sal , 1tsr , 1tup , 1uol , 1ycs , 2ac0 , 2ady , 2ahi , 2ata , 2b3g , 2bim , 2bin , 2bio , 2bip , 2biq , 2fej , 2gs0 , 2h1l , 2j1w , 2j1x , 2j1y , 2j1z , 2j20 , 2j21 , 2ocj , 3sak

Properties of human protein
Mass / length primary structure 393 amino acids
Cofactor Zn 2+
Isoforms 2
Identifier
Gene names TP53  ; LFS1; TRP53; p53
External IDs
Occurrence
Homology family TP53
Parent taxon Vertebrates

The p53 protein can be measured in increased quantities in many types of degenerate cells. It is also present in normally growing cells. However , p53 is hardly or not at all to be found in resting cells . The gene coding for p53 is mutated in many tumor types . In some, but not all, tumors, the protein appears to act as a tumor suppressor . p53 plays a role in regulating the cell cycle , where it slows down the activity of a number of genes. It is also found in all vertebrates .

p53 was independently discovered in 1979 by Albert B. DeLeo, David P. Lane, and Arnold Levine . As a transcription factor after DNA damage, the human tumor suppressor p53 regulates the expression of genes that are involved in the control of the cell cycle, in the induction of apoptosis ( programmed cell death ) or in DNA repair . Because of this property, p53 is referred to in the literature as the “guardian of the genome ”. The special medical importance is explained by the finding that p53 is mutated in 50% of all human tumors. The loss of p53 function therefore plays a critical role in the development of cancer , but it is not the causative trigger. p53 was voted "Molecule of the Year" in 1993 due to its importance.

Functions of p53

p53 got its name because of the apparent molecular mass of 53  kDa on an SDS-PAGE gel. The associated gene, the TP53 tumor suppressor gene, is located on chromosome 17p13.1 . To distinguish it from the protein, it is written in italics (TP53 was previously a synonym for human p53). The p53 protein is inherently unstable, but is regularly "replicated". However, if the DNA is damaged, such as a double-strand break, which would cause replication or mitosis to proceed incorrectly, p53 is post-translationally stabilized within 30 minutes , as a result of which p53 accumulates in the cell.

The accumulation of p53 has many consequences. On the one hand, DNA repair mechanisms are set in motion, on the other hand, the cell cycle is stopped. The latter happens because p53, as a transcription factor, induces the production of the protein p21 . p21 in turn inhibits both the cyclin D / CDK4 / 6 complex and the cyclin E / CDK2 complex. These are actually needed to release another transcription factor (E2F) bound by the protein pRB , which would continue the cell cycle. The p53 gives the cell time to repair itself before dividing. If the DNA is okay again, the p53 level drops again, p21 is no longer transcribed and after a while the cell cycle continues.

However, if p53 accumulates too much and other factors are added, p53 activates genes of the Bcl2 family (in particular the apoptosis regulator BAX), which in turn trigger caspases in the form of a signal cascade and thus lead to apoptosis (programmed cell death). Accordingly, p53 is like a kind of brake that is necessary to prevent cells from uncontrolled growth and further damage, and the mutation of which leads to increased cell division.

Another function of p53 is that it apparently controls the human pregnancy hormone hCG , as scientists from the University of Leipzig were able to show.

Damage to p53

p53 is a key protein of enormous importance. A defect therefore has a major damaging effect. As far as we know today, it is generally point mutations that lead to a loss of function. As a result of this loss, it is neither possible to stop the cell cycle for DNA repair nor to initiate apoptosis. Even if the DNA is damaged, the cells begin to divide uncontrollably, leading to tumor formation. Furthermore, the loss of functional p53 leads to a loss of the ability to synthesize cytochrome C oxidase 2. As a result, the cyclooxidase-2 subunit can no longer be incorporated into the cyclooxidase protein complex (complex IV of the respiratory chain). The cancer cell loses the metabolism of aerobic respiration, but goes over to anaerobic glycolysis to generate energy.

Below is a list of diseases that are exclusively or primarily due to mutations in TP53 (the p53 gene).

illness Frequency of the p53 mutation OMIM Remarks
Li Fraumeni syndrome type 1 70 percent of all cases are congenital 151623
Adrenal carcinoma 88 percent of all cases are congenital 202300 Consequence of Li Fraumeni Syndrome
Esophageal cancer 20 of 26 (1 allele) 133239 heaped in northern China
Nasopharyngeal carcinoma 4 out of 41 from Hong Kong and Guangxi 161550 Heaped 100 times in southern China

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

Patients born with Li Fraumeni syndrome have an inherited mutation in TP53 . For example, people with this mutation develop various tumors, such as breast cancer , leukemia , brain tumors and much more, in early childhood . The cause of the cancer, however, is probably not the mutation of TP53 itself, but the high rate of cell division during embryonic growth, despite defects in the DNA, so that damage can accumulate and other genes that regulate cell growth can be damaged. As researchers from Heidelberg in 2012 in the scientific journal Cell describes have tumors in patients with congenital TP53 - mutations beyond heaped features of catastrophic chromosomal rearrangements ( chromothripsis on). TP53 mutations could either trigger this massive genetic damage or prevent cell death by means of apoptosis , despite massive destruction of the chromosome structure . Since every X-ray examination or chemotherapy increases the mutation rate, both the diagnosis and the treatment of patients with Li-Fraumeni syndrome are particularly difficult.

In addition to spontaneously occurring mutations, there are also other causes of damage to p53 or its functions. There are tumor-inducing viruses (so-called oncoviruses ) that inhibit p53, break it down or accelerate its natural breakdown. Viruses use this strategy because viral diseases can also trigger apoptosis and thus prevent the viruses from spreading.

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

Relationship between p53 and life expectancy

Experiments on fruit flies indicate that an artificially reduced activity of the anti-tumor protein has a positive effect on the lifespan of the test animals. However, if the protein behaves more actively than normal (overactive), the treated fruit flies age much faster than usual. The same thing was observed in mice. However, the mechanism itself has not yet been clarified.

During the (often rapid) formation of antlers and horns of hornbeams , p53 prevents excessive growth; at the same time, the animals have a five-fold lower cancer rate compared to other mammals .

See also

literature

Web links

Commons : Tumor suppressor protein p53  - Collection of pictures, videos and audio files

Individual evidence

  1. ↑ Swiss Institute of Bioinformatics (SIB): PROSITE documentation PDOC00301. Retrieved September 20, 2011 .
  2. ^ DP Lane, LV Crawford: T antigen is bound to a host protein in SV40-transformed cells. In: Nature. Volume 278, Number 5701, March 1979, pp. 261-263, ISSN  0028-0836 . PMID 218111 .
  3. ^ DI Linzer, AJ Levine: Characterization of a 54K dalton cellular SV40 tumor antigen present in SV40-transformed cells and uninfected embryonal carcinoma cells. In: Cell. Volume 17, Number 1, May 1979, pp. 43-52, ISSN  0092-8674 . PMID 222475 .
  4. ^ DP Lane: Cancer. p53, guardian of the genome. In: Nature. Volume 358, Number 6381, July 1992, pp. 15-16, ISSN  0028-0836 . doi : 10.1038 / 358015a0 . PMID 1614522 .
  5. ^ Landes Bioscience November 1, 2011
  6. ↑ S. Matoba, JG Kang, WD Patino, A. Wragg, M. Boehm, O. Gavrilova, PJ Hurley, F. Bunz, PM Hwang: p53 regulates mitochondrial respiration. In: Science. Volume 312, number 5780, June 2006, ISSN  1095-9203 , pp. 1650-1653, doi : 10.1126 / science.1126863 , PMID 16728594 .
  7. ↑ RF Boynton et al .: Loss of heterozygosity involving the APC and MCC genetic loci occurs in the majority of human esophageal cancers. Proc. Nat. Acad. Sci. 89 / - / 1992. Pp. 3385-3388. PMID 1565631
  8. ↑ F. Chakrani et al .: Mutations clustered in exon 5 of the p53 gene in primary nasopharyngeal carcinomas from southeastern Asia. Int. J. Cancer 61 / - / 1995. Pp. 316-320. PMID 7729941
  9. ↑ Riede, Werner, Schaefer: General and special pathology. 5th completely revised edition, Thieme Verlag
  10. ↑ T. Rausch et al .: Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell 148 / - / 2012. Pp. 59-71. PMID 22265402
  11. ↑ J. Bauer et al. In Current Biology
  12. ↑ G. Ferbeyre, SW Lowe: Aging: The price of tumor suppression? Nature 415, 26-27 (2002)
  13. ↑ S. D. Tyner et al. a .: p53 mutant mice that display early aging-associated phenotypes. In: Nature. 415, 2002, pp. 45-53. doi: 10.1038 / 415045a PMID 11780111
  14. ↑ Y. Wang et al .: Genetic basis of ruminant headgear and rapid antler regeneration Science 364eaav6335 (2019) doi: 10.1126 / science.aav6335 PMID 31221830