engleski

The role of p73, p53 gene homologue, in tumors

The p73 gene encodes a protein with a significant sequence homology and consequently functional similarities with p53. The p73 can bind to p53 DNA binding sites and transacitvate p53 target genes and induce cell cycle arrest and apoptosis. Despite structural similarities with p53 there are differences in genomic organization of the genes. In contrast to p53, p73 gene shows many splice variants encoding a number of different N- and C- terminal isoforms. C-terminal splice variants create the isoforms of different lengths that do not vary much in their role in tumorigenesis. On the other hand, p53 family member p73 generates transactivating forms (TAp73) as well as a number of N-terminally truncated, transactivation-deficient transdominant isoforms. There are three such isoforms called deltaNp73, Ex2p73 and Ex2/3p73. Importantly, deltaNp73, which can be derived either from the TA promoter or an alternative promoter in intron 3, is frequently overexpressed both on the RNA and protein level in a variety of human tumors. The differences between p53 and p73 in structure trigger the functional differences. Unlike p53, p73 is rarely mutated in human primary tumors, p73-knock out mouse doesn’ t show the tumorigenic phenotype. There is striking evidence that  TAp73 forms might act as oncogenes in primary tumors. There is potential use of p73 in gene therapy. The cervical cancers caused by HPV are resistant to p53 gene therapy becuase HPV-E6 protein degrades p53. However, p73 is resistant to HPV-E6-caused proteolysis, induces apoptosis and is potent inhibitor of cancer colony growth. Recently was demonstrated that some cancer cells, resistant to p53-mediated cell death undergo apoptosis after adenovirus-mediated p73 gene transfer. Since there is striking evidence that deltaTAp73 forms are overexpressed in human tumors, the gene therapy approach that applies siRNA technology might inhibit their potential oncogenic function. The TAp73 protein is induced by wide variety of chemotherapeutic agents. The overexpression of antiapoptotic p73 isoforms or mutated p53 can block chemotherapy-induced apoptosis. The blocking of such dominant negative isoforms and/or mutated p53 by siRNA could restore chemosensitivity to chemotherapeutic agents.

p73; gene therapy; chemotherapy

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