Cancer GeneTherapy to Restore P53 Function: Augmentation the Wild Type or Silencing the Mutant Gene?

Millions of people are living with cancer having specific mutation in p53 gene while everysingle person is truly unique in genetic basis or clinical manifestation. The gene encodestranscription factor p53, which plays a central role in regulating cell cycle progression,senescence, differentiation, DNA repair and apoptosis in response to DNA damage or otherstress signals. P53 activity is up regulated to initiate a cascade of biological events thatultimately results in prevention of tumor development. Mutations in p53 abrogate normaltumor suppressor functions, contributing to the survival and proliferation of abnormal cells.Cancer cells containing mutant p53 are associated with more aggressive disease, increasedresistance to chemotherapy and radiation therapy, and poor prognosis.. However the majorityof p53 mutations are missense and great number of these mutants represent GOF (Gain ofFunction) effect resulting increased invasion and metastasis in tumors. These mutationsconfer a dominant-negative activity over the remaining wild-type allele by functionallyinactive hetero-oligomers interactions of the mutants with the wild-type protein. Increasingevidence indicates that many p53 mutants also gain new oncogenic properties that areindependent from wild-type p53. Several factors including type of p53 mutations in cancersmay limit the efficacy and application of p53 gene therapy. As a result, there is a great interestin therapeutic strategies aimed at restoring the function of p53 for the treatment of cancer.Increasing evidence demonstrate that Silencing GOF mutations (targeted antisense therapy)reduce the transactivation activity of mutant p53 and induce apoptosis in cells bearing thesemutations then provide a potential strategy to inhibit the oncogenic functions of mutant p53and improve mutant p53-targeted cancer therapies.

Keywords:

Apoptosis , Cancer , Gene Therapy , P53 , Dominant , Negative Mutations