Tumor suppressor genes

Tumor suppressor genes (they cause cancer when they lose function):

These genes contribute also to cell growth and or differentiation. They play also important roles in the apoptosis process and cell-to-cell adhesion. To the contrary, of oncogenes tumor suppressors contribute to cancer formation when their function is lost. Examples of tumor suppressor genes are Rb, p53 and its family of proteins p63 and p73.

p53 and its family members p73 and p63

Tumor suppressors act to maintain tissue homeostasis, that is, to control the number and behavior of cells in a particular tissue within an organism (Hussain and Harris 1998). To do so, they typically regulate one or more of the processes preventing aberrant proliferation (Vogelstein et al., 2000; Vousden and Lu 2002). The power of p53 can be estimated by the fact that a single gene is responsible for two cellular conditions, which are as different as can be the life and the death of a cell.

p53 acts in response to diverse forms of cellular stress to promote cell-cycle checkpoints, DNA repair, cellular senescence and apoptosis. Thus, p53 suppresses tumor development by preventing a potential cancerous cell from passing on its defective DNA code to the next generation of cells. On the other hand, malfunctions of p53 function promote checkpoint defects, cellular immortalization, genomic instability and inappropriate survival, allowing the continued proliferation and evolution of damaged cells. Given the profound proliferative advantage produced by loss of p53 function, it is not surprising that p53 is the most commonly inactivated tumor suppressor gene in human cancer (Hussain and Harris 1998; Beroud and Soussi 2003).

p53 history of discovery:

In 1979, the p53 protein was discovered thanks to virologic and serologic concerned studies. A 55-kDa protein was first discovered to co-precipitate with the large-T antigen of SV40 (Simian Virus 40) transformed cells. Then, the observation that this protein was also overexpressed in uninfected embryonic carcinoma cells suggested that it could be part of the cellular genome, and that its synthesis and/or stability could be stimulated by virus infection or cell transformation (Chang et al., 1979; Kress et al., 1979; Lane and Crawford 1979; Linzer and Levine 1979; Melero et al., 1979). By serology, it was observed that the humoral response of mice to tumorigenic cell lines, as well as of animals bearing several types of tumors, was directed toward the p53 protein, as supported by the high level of anti-p53 antibodies in their sera. Interestingly, the first described antibodies against human p53 protein were elicited in 9% of breast cancer patient sera, followed by their observation in sera of children with a wide variety of cancers (De Leo et al., 1979; Kress et al., 1979; Melero et al., 1979; Rotter et al., 1980; Crawford et al., 1982; Caron de Fromentel et al., 1987).

 
Owing to these observations, p53 was first thought to be a proto-oncogene and, only 11 years later, it was recognized as a tumor suppressor gene. Indeed, observations from early studies showed that p53 protein level reached a peak just near to DNA replication (Milner and McCornick, 1980; Reich and Levine, 1984; Calabretta et al., 1986), thus suggesting that p53 was involved in cell growth and proliferation. The finding that p53 could immortalize normal cells, and sensitize them for transformation in response to Ras oncogene, caused the classification of p53 as a nuclear dominant oncogene (Eliyahu et al., 1984; Jenkins et al., 1984; Parada et al., 1984; Jenkins et al., 1985).

Nonetheless, other studies showed that some murine p53 cDNA clones failed to cooperate with activated Ha-ras and that some rearranged forms of the protein provided selective growth advantage during the development of Friend leukemia in vivo (Mowat et al., 1985; Munroe et al., 1988). Examination of all the available murine p53 cDNA clones revealed sequence differences not linked to polymorphism, important for both the conformation and biological activity of the protein (Finlay et al., 1988; Eliyahu et al., 1989). These observations were supported by the finding that transgenic mice carrying a mutant p53 gene (TP53) develop many types of cancer, with a high proportion of sarcomas (Lavigueur et al., 1989).

Moreover, a germ-line mutation in TP53 leads to a dominant autosomic disease, the Li-Fraumeni syndrome, which enhances dramatically predisposition to sarcoma, breast cancer or brain tumors (Malkin et al., 1990; Srivastava et al., 1990). In all cases, there was a strict correlation between transmission of the p53 mutated allele and development of cancer; in those patients lacking TP53 mutations, alterations in the CHK2 kinase (an important p53 activator in response to DNA damage) have been described (Bell et al., 1999). Thus the wild type p53 acts as a tumor suppressor gene, while some of its mutants exhibit a transdominant phenotype, able to associate with the wild-type protein forming an inactive heteroligomer (Milner and Medcalf 1991).