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 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 counterpart, 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 that cause cellular transformations have also been found to result in increased p73 expression. Furthermore, recent finding are suggesting that over-expression of transcription factors involved in cell cycle regulation and synthesis of DNA in mammalian cells (e.g.: E2F-1) induces the expression of p73. Many researchers believe that these results imply that p73 may not be a tumor suppressor but rather an oncoprotein. 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 over-expressed and ultimately plays a role in tumorigenesis.
Genes of the p53 family are known to be complex. The viral oncoproteins (e.g. Adenovirus E1B) that efficiently inhibit p53 function are unable to inactivate p73, and those that 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
- A naturally occurring p73 mutation in a p73-p53 double-mutant lung cancer cell line encodes p73α protein with a dominant-negative function
- TP73 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)
Further reading
- Kaghad M, Bonnet H, Yang A, et al. (August 1997). "Monoallelically expressed gene related to p53 at 1p36, a region frequently deleted in neuroblastoma and other human cancers". Cell 90 (4): 809–19. doi:10.1016/S0092-8674(00)80540-1. PMID 9288759.
- Levrero M, De Laurenzi V, Costanzo A, Gong J, Wang JY, Melino G (May 2000). "The p53/p63/p73 family of transcription factors: overlapping and distinct functions". J. Cell. Sci. 113 (10): 1661–70. PMID 10769197.
- Pozniak CD, Radinovic S, Yang A, McKeon F, Kaplan DR, Miller FD (July 2000). "An anti-apoptotic role for the p53 family member, p73, during developmental neuron death". Science 289 (5477): 304–6. doi:10.1126/science.289.5477.304. PMID 10894779.
- Yang A, Walker N, Bronson R, et al. (March 2000). "p73-deficient mice have neurological, pheromonal and inflammatory defects but lack spontaneous tumours". Nature 404 (6773): 99–103. doi:10.1038/35003607. PMID 10716451.
- Kaelin WG (1999). "The emerging p53 gene family.". J. Natl. Cancer Inst. 91 (7): 594–8. doi:10.1093/jnci/91.7.594. PMID 10203277.
- Davis PK, Dowdy SF (2001). "p73.". Int. J. Biochem. Cell Biol. 33 (10): 935–9. doi:10.1016/S1357-2725(01)00073-5. PMID 11470228.
- Salomoni P, Pandolfi PP (2002). "The role of PML in tumor suppression.". Cell 108 (2): 165–70. doi:10.1016/S0092-8674(02)00626-8. PMID 11832207.
- Melino G (2004). "p73, the "assistant" guardian of the genome?". Ann. N. Y. Acad. Sci. 1010: 9–15. doi:10.1196/annals.1299.002. PMID 15033688.
- Jacobs WB, Walsh GS, Miller FD (2005). "Neuronal survival and p73/p63/p53: a family affair.". The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry 10 (5): 443–55. doi:10.1177/1073858404263456. PMID 15359011.
- Rossi M, Sayan AE, Terrinoni A, et al. (2005). "Mechanism of induction of apoptosis by p73 and its relevance to neuroblastoma biology.". Ann. N. Y. Acad. Sci. 1028: 143–9. doi:10.1196/annals.1322.015. PMID 15650240.
- Dobbelstein M, Strano S, Roth J, Blandino G (2005). "p73-induced apoptosis: a question of compartments and cooperation.". Biochem. Biophys. Res. Commun. 331 (3): 688–93. doi:10.1016/j.bbrc.2005.03.155. PMID 15865923.
- Ramadan S, Terrinoni A, Catani MV, et al. (2005). "p73 induces apoptosis by different mechanisms.". Biochem. Biophys. Res. Commun. 331 (3): 713–7. doi:10.1016/j.bbrc.2005.03.156. PMID 15865927.
- Harms KL, Chen X (2006). "p19ras brings a new twist to the regulation of p73 by Mdm2.". Sci. STKE 2006 (337): pe24. doi:10.1126/stke.3372006pe24. PMID 16738062.
- Marabese M, Vikhanskaya F, Broggini M (2007). "p73: a chiaroscuro gene in cancer.". Eur. J. Cancer 43 (9): 1361–72. doi:10.1016/j.ejca.2007.01.042. PMID 17428654.
- Levy D, Adamovich Y, Reuven N, Shaul Y (2007). "The Yes-associated protein 1 stabilizes p73 by preventing Itch-mediated ubiquitination of p73". Cell Death and Differentiation 14 (4): 743–51. doi:10.1038/sj.cdd.4402063. PMID 17110958.
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