9/24/2023 0 Comments Aaron prodeus![]() ![]() Classification of 184 p53 mutants are categorized into monomeric, dimeric and tetrameric protein species as predicted from crosslinking experiments. (A) Plot of transcriptional activity of selected p53 target genes performed in yeast using a missense mutation library in the OD of p53 (derived from data by Kato et al.). Retrospective analysis of transcriptional profiles of p53 oligomeric variants reveals that dimeric p53 mutants display selective gene expression. (E) Cellular expression of p53 oligomeric variants in H1299 cells at 24 hours (odd numbered lanes) and 48 hours (even numbered lanes) as analyzed by Western blot of cell lysates using an anti-p53 antibody (DO-1). (D) Schematic drawing of wt p53 and oligomeric variants. Western blot detection of p53 monomers and oligomers resolved by SDS PAGE following lysate treatment with 0.025% glutaraldehyde. (C) Glutaraldehyde crosslinking of p53 species isolated from H1299 cell lysates. A ribbon model of p53-CR illustrates the constructive charge interactions within the dimer-dimer interface of the p53 OD. (B) Amino acid sequence of the OD from p53-CR contains 3 charge-reversal mutations at positions 343, 346 and 351. Ribbon models of the predicted structure for 2 tandem ODs of p53-2OD as a dimer of monomers (blue and gray) were generated by homology modeling of the 1PES structure using SWISS-MODEL. (A) Amino acid sequence of the modified OD from p53-2OD contains 2 ODs (residues 310–360 of wt p53) separated by a glycine-threonine flexible linker. This study suggests that the most abundant oligomeric species of p53 present in resting cells, namely p53 dimers, neither promote cell growth or cell death and that shifting the oligomeric state equilibrium of p53 in cells toward monomers or tetramers is a key parameter in p53-based cell fate decisions.Īpoptosis cell cycle arrest cell fate oligomerization p53 tumor suppressor. In particular, the expression of pro-arrest CDKN1A and pro-apoptotic P53AIP1 genes are important cell fate determinants that are differentially regulated by the oligomeric state of p53. In contrast, p53 tetramers induce rapid apoptosis and cell growth arrest, while a monomeric variant is functionally inactive, supporting cell growth. ![]() We report that dimeric p53 variants are cytostatic and can arrest cell growth, but lack the ability to trigger apoptosis in p53-null cells. ![]() Here, we use 5 oligomeric variants of p53, including 2 novel p53 constructs, that yield either monomeric, dimeric or tetrameric forms of p53 and demonstrate that they induce distinct cellular activities and gene expression profiles that lead to different cell fate outcomes. How p53 chooses between these cell fate outcomes remains unclear. Activation of p53 through tetramerization is required for its tumor suppressive function by inducing transcriptional programs that lead to cell fate decisions such as cell cycle arrest or apoptosis. These mutations typically alter the oligomeric state of p53 and impair its transcriptional activity. Mutations in the oligomerization domain of p53 are genetically linked to cancer susceptibility in Li-Fraumeni Syndrome.
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