P73


P73

p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein. This is explained by splice variants, and an alternative promoter in the DNA sequence.

p73, also known as tumor protein 73 (TP73), protein was the first identified homologue of the tumor suppressor gene, p53. Like p53, p73 has several variants. It is expressed as distinct forms differing at either at the C- or the N-terminus. Currently, six different C-terminus splicing variants have been found in normal cells. The p73 gene encodes a protein with a significant sequence homology and a functional similarity with the tumor suppressor p53. The over-expression of p73 in cultured cells promotes a growth arrest and/or apoptosis similarly to p53.

The p73 gene has been mapped to a chromosome region (1p36. 2-3) a locus which is commonly deleted in various tumor entities and human cancers. Similar to p53 the protein product of p73 induces cell cycle arrest or apoptosis, hence its classification as a tumor suppressor. However unlike its counter part, p73 is infrequently mutated in cancers. Perhaps, even more shocking is the fact that p73 – deficient mice do not show a tumorigenic phenotype. A deficiency of p53 almost certainly leads to unchecked cell proliferation and is noted in 60% of cancers.

Analyses of many tumors typically found in humans including breast and ovarian cancer show a high expression of p73 when compared to normal tissues in corresponding areas. Adenoviruses which cause cellular transformations have also been found to result in increased p73 expression. Furthermore, recent finding are suggesting that deregulated over expression of transcription factors within the body involved in cell cycle regulation and synthesis of DNA in mammalian cells (i.e.: E2F-1), induces the expression of p73. Many researchers believe that these results are beginning to suggest that p73 may not be a tumor suppressor but rather an oncoprotien. Some suggest that the TP73 locus encodes both a tumor suppressor (TAp73) and a putative oncogene (ΔNp73). This is a strong theory and causes much confusion as it is unknown which of the two p73 variants is being over expressed and ultimately plays a role in tumorigenesis.

Genes of the p53 family are known to be complex. The viral oncoproteins (i.e.: Adenovirus 1EB) which efficiently inhibit p53 function, are unable to inactivate p73 and those which seem to inhibit p73 have no effect on p53.

Debate persists about the exact function of p73. Recently it has been reported that p73 is enriched in the nervous system and that the p73-deficient mice, which do not exhibit an increased susceptibility to spontaneous tumorigenesis, have neurological and immunological defects. These results have been expanded and it has also been shown that p73 is present in early stages of neurological development and neuronal apoptosis by blocking the proapoptotic function of p53. This strongly implicates p73 as playing a large role in cellular differentiation.

External links

* [http://www.blackwell-synergy.com/doi/abs/10.1111/j.1349-7006.2003.tb01508.x A naturally occurring p73 mutation in a p73-p53 double-mutant lung cancer cell line encodes p73α protein with a dominant-negative function]
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Further reading

*Kaghad, M., H. Bonnet, A. Yang, L. Creancier, J. C. Biscan, A. Valent, A. Minty, P. Chalon, J. M. Lelias, X. Dumont, P. Ferrara, F. McKeon, and D. Caput. 1997. Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers. Cell 90:809-819. Entrez Pubmed|9288759
* Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G. (2000). J. Cell Sci., 113: (10). 1661-1670 Entrez Pubmed|10769197
*Pozniak, C. D., S. Radinovic, A. Yang, F. McKeon, D. R. Kaplan, and F. D. Miller. 2000. An anti-apoptotic role for the p53 family member, p73, during developmental neuron death. Science 289:304-306 Entrez Pubmed|10894779
*Yang, A., N. Walker, R. Bronson, M. Kaghad, M. Oosterwegel, J. Bonnin, C. Vagner, H. Bonnet, P. Dikkes, A. Scharpe, F. McKeon, and D. Caput. 2000. p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours. Nature 404:99-103. Entrez Pubmed|10716451PBB_Further_reading
citations =
*cite journal | author=Kaelin WG |title=The emerging p53 gene family. |journal=J. Natl. Cancer Inst. |volume=91 |issue= 7 |pages= 594–8 |year= 1999 |pmid= 10203277 |doi=
*cite journal | author=Davis PK, Dowdy SF |title=p73. |journal=Int. J. Biochem. Cell Biol. |volume=33 |issue= 10 |pages= 935–9 |year= 2001 |pmid= 11470228 |doi=
*cite journal | author=Salomoni P, Pandolfi PP |title=The role of PML in tumor suppression. |journal=Cell |volume=108 |issue= 2 |pages= 165–70 |year= 2002 |pmid= 11832207 |doi=
*cite journal | author=Melino G |title=p73, the "assistant" guardian of the genome? |journal=Ann. N. Y. Acad. Sci. |volume=1010 |issue= |pages= 9–15 |year= 2004 |pmid= 15033688 |doi=
*cite journal | author=Jacobs WB, Walsh GS, Miller FD |title=Neuronal survival and p73/p63/p53: a family affair. |journal=The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry |volume=10 |issue= 5 |pages= 443–55 |year= 2005 |pmid= 15359011 |doi= 10.1177/1073858404263456
*cite journal | author=Rossi M, Sayan AE, Terrinoni A, "et al." |title=Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology. |journal=Ann. N. Y. Acad. Sci. |volume=1028 |issue= |pages= 143–9 |year= 2005 |pmid= 15650240 |doi= 10.1196/annals.1322.015
*cite journal | author=Dobbelstein M, Strano S, Roth J, Blandino G |title=p73-induced apoptosis: a question of compartments and cooperation. |journal=Biochem. Biophys. Res. Commun. |volume=331 |issue= 3 |pages= 688–93 |year= 2005 |pmid= 15865923 |doi= 10.1016/j.bbrc.2005.03.155
*cite journal | author=Ramadan S, Terrinoni A, Catani MV, "et al." |title=p73 induces apoptosis by different mechanisms. |journal=Biochem. Biophys. Res. Commun. |volume=331 |issue= 3 |pages= 713–7 |year= 2005 |pmid= 15865927 |doi= 10.1016/j.bbrc.2005.03.156
*cite journal | author=Harms KL, Chen X |title=p19ras brings a new twist to the regulation of p73 by Mdm2. |journal=Sci. STKE |volume=2006 |issue= 337 |pages= pe24 |year= 2006 |pmid= 16738062 |doi= 10.1126/stke.3372006pe24
*cite journal | author=Marabese M, Vikhanskaya F, Broggini M |title=p73: a chiaroscuro gene in cancer. |journal=Eur. J. Cancer |volume=43 |issue= 9 |pages= 1361–72 |year= 2007 |pmid= 17428654 |doi= 10.1016/j.ejca.2007.01.042

*cite journal | author=Levy D, Adamovich Y, Reuven N, Shaul Y|title=The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73 |journal=Cell Death and Differentiation |volume=14 |issue= 4 |pages= 743–51 |year= 2007 |pmid= 17110958 |doi= 10.1038/sj.cdd.4402063

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