p53 gain-of-function: tumor biology and bioinformatics come together.
p53 is typically viewed as a tumor suppressor. However, many missense somatic and germline mutations in the p53 gene cause gain-of-function whereby p53 acquires novel biochemical activities, such as the ability to transactivate transcription of new genes or to mediate new regulatory protein-protein interactions. Several recent studies show that at least some gain-of-function mutations of p53 are biologically relevant leading to a change in the tumor phenotype. Independent bioinformatic analysis of somatic mutation spectra of the p53 gene yields three lines of evidence supporting the notion that gain-of-function could be the prevalent mode of p53 evolution in tumors. (1) The hotspots in the p53 gene show signs of intensive positive selection. (2) The hotspots are located primarily in functionally important motifs of the DNA-binding domain of p53 which are highly conserved in interspecies evolution. (3) The spectra of hotspots significantly differ among various tumor types and the germline (Li-Fraumeni syndrome); in addition to the hotspots shared by the germline and some of the tumors, many are tumor-specific. The latter observation suggests an unexpected level of complexity of p53 evolution in tumors, with distinct novel function gained in different tumors.
Koonin
Eugene V
EV
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. koonin@ncbi.nlm.nih.gov
Rogozin
Igor B
IB
Glazko
Galina V
GV
D000818:Animals; D019295:Computational Biology; D004273:DNA, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D020125:Mutation, Missense; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53