p53 Information

p53 information

p53 story

p53 discovery

p53 as an oncogene

p53 as a tumor suppressor gene

p53 in development






p53 monoclonal antibodies

p53 pathways

p53 gene

p53 protein(s)

mdm family

p63/p73 protein(s)

p53 evolution

p53 polymorphism

p53 and cancer

mouse models

ASPP family





 p53 as a Tumour suppressor

p53 in Friend murine erythroleukemia

 In these tumors induced by the Friend virus, the p53 gene found in the tumor cells is very often rearranged, leading to an absence of expression or the synthesis of a truncated or mutant protein (Mowat et al. 1985) The mutation often affects one of the conserved blocks of the protein (Munroe et al. 1988). In all cases studied, the second allele is either lost through loss of the chromosome, or inactived by deletion. In this tumor model, functional inactivation of the p53 gene seems to confer a selective growth advantage to erythroid cells during the development of Friend leukemia in vivo.



There are mutations in the various murine p53 cDNA clones

 The finding that one murine p53 cDNA clone isolated from the F9 cell failed to cooperate with an activated Ha-ras gene was another clue that the p53 cDNA clones differ from one another in their behavior (Finlay et al. 1988). Examination of all murine p53 cDNA clones available revealed several codon changes which were primarily assumed to be due to polymorphism. However, comparison of these sequence differences with p53 from lower species indicated that some of them occur in highly conserved regions (Soussi et al. 1990; Soussi et al. 1987), a feature which is not linked to polymorphism. Careful reinvestigation of all sequences led to the conclusion that the F9 cDNA clone was a wild type, while most of the others used in transfection experiments contain point mutations which activate their transforming properties.



Wild type p53 has antiproliferative properties and does not cooperate with Ha-ras

 A new set of experiments has shown that cotransfection of a plasmid encoding wild type p53 reduced the transformation potential of plasmids encoding p53 and an activated Ha-ras gene (Eliyahu et al. 1989; Finlay et al. 1989). Furthermore, wild type p53 was shown to suppress transformation by a mixture of E1A or myc and an activated Ha-ras gene. These transformation experiments indicate that wild type p53 is a suppressor of cell transformation in vitro.



p53 gene is mutated in a wide variety of human cancer

The expression of p53 in different human cancers or in tumor cell lines has long been under study by several different investigators. This expression is often high, but no precise explanations exist for this phenomenon because apart from the case of several osteosarcomas, no gene rearrangements, detectable by Southern blotting, have been detected. Genetic analysis of colorectal cancer reveals a very high rate of heterozygous loss of the short arm of chromosome 17, which carries the p53 gene (Vogelstein et al. 1988). PCR analysis and sequencing of the remaining p53 allele shows that it often contains a point mutation (Baker et al. 1989). Similar observations have been made in the case of lung cancer (Takahashi et al. 1989). On the heels of these initial observations have come several hundred reports of alterations of the p53 gene in all types of human cancer (see below). In many cases these mutations are accompanied by a heterozygous loss of the short arm of chromosome 17




Germline mutation of the p53 gene are found in Li-Fraumeni patients

Transgenic mice carrying a mutant p53 gene develop many types of cancer, with a high proportion of sarcomas (Lavigueur et al. 1989). This observation led various authors to study patients with Li-Fraumeni syndrome. This syndrome presents as a familial association of a broad spectrum of cancers including osteosarcomas, breast cancer, soft tissue sarcoma and leukemias, appearing at a very early age. Statistical analysis predicts that 50 % of these individuals will have a tumor before the age of 30, and 90 % before the age of 70. Germ-line mutations in the p53 gene have been found in several families with this syndrome (Malkin et al. 1990; Srivastava et al. 1990). In all cases there is a strict correlation between transmission of the mutant allele and development of a cancer.



Why micro-injection of p53 monoclonal antibody induces a growth arrest ?

The carboxy-terminus of Hp53 has been shown to play an important role in controlling the specific DNA binding function. Wild type p53 is found in a latent form that does not bind to DNA. The specific DNA binding activity was shown to be activated by various pathways: phosphorylation (Hupp et al., 1992), antibody specific for the carboxy-terminus of the protein (Hupp et al., 1992), small peptides which could mimic the carboxy-terminus of the p53 (Hupp et al., 1995), short single stranded DNA (Jayaraman & Prives, 1995), deletion of the last 30 amino-acids (Hupp et al., 1992) and the interaction with a cellular protein (Jayaraman et al., 1997).


This observation suggest that micro-injection of antibodies such as PAb421 induces an activation of the transcriptional activity of p53. Such hypothesis have been confirmed (Hupp et al., 1995)



Wild type p53 as a tumor suppressor gene and mutant p53 as a dominant oncogene ?

 Taken together, these data made it possible to define the p53 gene as a tumor suppressor gene. Yet unlike the Rb gene, which is the archetype of the tumor suppressor genes, the p53 gene has some original features. In particular, more than 95 % of alterations in the p53 gene are point mutations that produce a mutant protein, which in all cases has lost its transactivational activity (see above). Nevertheless, the synthesis of these mutant p53 proteins is not harmless for the cell. In paticular, it has been shown that some p53 mutants (depending on the site of mutation) exhibit a transdominant phenotype and are able to associate with wild-type p53 (expressed by the remaining wild-type allele) to induce the formation of an inactive heteroligomer (Milner and Medcalf 1991). Moreover, cotransfection of mutant p53 with an activated ras gene shows that some p53 mutants have high, dominant oncogenic activity (Halevy et al. 1990). These observations led to the proposal that several classes of mutant p53 exist, according to the site of mutation and its phenotype (Michalovitz et al. 1991): i) null mutations with totally inactive p53 that do not directly intervene in transformation; ii) dominant negative mutations with a totally inactive p53 that is still able to interfere with wild-type p53 expressed from the wild-type allele, and iii) positive dominant mutations where the normal function of p53 is altered but in this case the mutant p53 acquires an oncogenic activity that is directly involved in transformation.


• Baker SJ, Fearon ER, Nigro J, Hamilton S, Preisinger AC, Jessup JM, vanTuinen P, Ledbetter DH, Barker DF, Nakamura Y, Whyte R and Vogelstein B (1989) Chromosome 17 deletions and p53 gene mutations in colorectal carcinomas. Science 244: 217-221.
• Eliyahu D, Michalovitz D, Eliyahu S, Pinhasikimhi O and Oren M (1989) Wild-Type p53 can inhibit oncogene-mediated focus formation. Proc. Natl. Acad. Sci. USA 86: 8763-8767.
• Finlay CA, Hinds PW and Levine AJ (1989) The p53 proto-oncogene can act as a suppressor of transformation. Cell 57: 1083-1093.
• Finlay CA, Hinds PW, Tan TH, Eliyahu D, Oren M and Levine AJ (1988) Activating mutations for transformation by p53 produce a gene product that forms an hsc70-p53 complex with an altered half life. J. Virol. 8: 531-539.
• Halevy O, Michalovitz D and Oren M (1990) Different tumor-derived p53 mutants exhibit distinct biological activities. Science 250: 113-116.
• Lavigueur A, Maltby V, Mock D, Rossant J, Pawson T and Bernstein A (1989) High incidence of lung, bone, and lymphoid tumors in transgenic mice overexpressing mutant alleles of the p53 oncogene. Mol. Cell. Biol. 9: 3982-3991.
• Malkin D, Li FP, Strong LC, Fraumeni JF, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA and Friend SH (1990) Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 250: 1233-1238.
• Michalovitz D, Halevy O and Oren M (1991) p53 mutations - gains or losses. J. Cell. Biochem. 45: 22-29.
• Milner J and Medcalf EA (1991) Cotranslation of activated mutant p53 with wild type drives the wild-type p53 protein into the mutant conformation. Cell 65: 765-774.
• Mowat M, Cheng A, Kimura N, Bernstein A and Benchimol S (1985) Rearrangements of the cellular p53 gene in erythroleukaemic cells transformed by Friend virus. Nature 314: 633-636.
• Munroe DG, Rovinski B, Bernstein A and Benchimol S (1988) Loss of highly conserved domain on p53 as a result of gene deletion during friend virus-induced erythroleukemia. Oncogene 2: 621-624.
• Soussi T, Caron de Fromentel C and May P (1990) Structural aspects of the p53 protein in relation to gene evolution. Oncogene 5: 945-952.
• Soussi T, Caron de Fromentel C, Méchali M, May P and Kress M (1987) Cloning and characterization of a cDNA from Xenopus laevis coding for a protein homologous to human and murine p53. Oncogene 1: 71-78.
• Srivastava S, Zou ZQ, Pirollo K, Blattner W and Chang EH (1990) Germ-line transmission of a mutated p53 gene in a cancer-prone family with li-fraumeni syndrome. Nature 348: 747-749.
• Takahashi T, Nau MM, Chiba I, Birrer MJ, Rosenberg RK, Vinocour M, Levitt M, Pass H, Gazdar AF and Minna JD (1989) p53 - a frequent target for genetic abnormalities in lung cancer. Science 246: 491-494.
• Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, Nacamura V, White R, Smits AM and Bos JL (1988) Genetic alterations during colorectal-tumor development. N. Engl. J. Med. 319: 525-532.

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