Tumor-derived p53 mutants induce oncogenesis by transactivating growth-promoting genes

MJ Scian, KER Stagliano, D Deb, MA Ellis… - Oncogene, 2004 - nature.com
MJ Scian, KER Stagliano, D Deb, MA Ellis, EH Carchman, A Das, K Valerie, SP Deb, S Deb
Oncogene, 2004nature.com
We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-
derived mutants. Using a colony formation assay, we found that the majority of the mutants
increased the number of colonies formed compared to the vector. Expression of tumor-
derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have
'gain of function'properties. We have studied the gene expression profile of cells expressing
tumor-derived p53-D281G to identify genes transactivated by mutant p53. We report the …
Abstract
We have studied the mechanism of mutant p53-mediated oncogenesis using several tumor-derived mutants. Using a colony formation assay, we found that the majority of the mutants increased the number of colonies formed compared to the vector. Expression of tumor-derived p53 mutants increases the rate of cell growth, suggesting that the p53 mutants have ‘gain of function’properties. We have studied the gene expression profile of cells expressing tumor-derived p53-D281G to identify genes transactivated by mutant p53. We report the transactivation of two genes, asparagine synthetase and human telomerase reverse transcriptase. Quantitative real-time PCR confirms this upregulation. Transient transfection promoter assays verify that tumor-derived p53 mutants transactivate these promoters significantly. An electrophoretic mobility shift assay shows that tumor-derived p53-mutants cannot bind to the wild-type p53 consensus sequence. The results presented here provide some evidence of a possible mechanism for mutant p53-mediated transactivation.
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