Sci. STKE, 30 May 2006
GENE EXPRESSION p53's Posttranslational Code
Phosphorylation and acetylation are posttranslational modifications that influence protein function. Not only are the structure and accessibility of chromatin influenced by these modifications but so are the transcription factors that bind DNA and regulate gene expression. The activity of p53, which is a transcriptional regulator, is controlled through posttranslational modifications that influence the stability of the protein, the localization of the protein, and its interactions with corepressors and coactivators. Knights et al. show that lysine 373 (K373) and lysine 320 (K320) appear to promote different p53 activities--K373 stimulates the proapoptotic activities of p53, and K320 promotes cell survival activities. The authors created a series of p53 mutants using glutamine (Q) to mimic acetylation at specific sites: p53Q373, p53Q320, and a mutant in which four lysines were replaced at Q320, 370, 372, and 373 (p53DM). Expression of p53Q320 or p53DM in cells that lacked endogenous p53 promoted G1 arrest and protected cells from apoptosis in response to DNA-damaging drugs (adozelesin or bizelesin) or inhibition of topoisomerase (etopside). In contrast, p53Q373 promoted transient arrest in G2/M and ultimately increased cell death in response to adozelesin, bizelesin, or etopside treatment. Coimmunoprecipitation experiments with the mutant p53 proteins or with acetylated p53 showed that acetylation of K373 or K320 promoted the interaction of p53 with different chromatin-remodeling enzymes. The data suggested that when acetylated at position K373, p53 interacted more strongly with corepressors and histone deacetylases. Microarray experiments comparing the gene-expression profiles of cells expressing wild-type p53, p53Q373, or p53Q320 showed that p53Q373 was a stronger repressor. Furthermore, the genes that were activated in the p53Q373 cells were proapoptotic, and genes that were repressed were associated with cell survival, which is consistent with the proapoptotic effect of p53Q373. The p53Q320 profile tended to be opposite that of the p53Q373 profile, with p53Q320 showing repression of genes associated with apoptosis and stimulation of genes associated with cell survival. Differences in the affinity of p53 acetylated at different sites (or the acetylation mimics) was observed at specific p53 target gene promoters in chromatin immunoprecipitation and electrophoretic mobility shift assays. p53Q320 exhibited a cytosolic localization, whereas p53Q373 was nuclear. Futhermore, the phosphorylation of sites in the N terminus of p53 was decreased in p53Q320 compared with wild-type p53, whereas p53Q373 exhibited more intense phosphorylation than did wild-type p53. Thus, the acetylation status of p53 appears to differentially control phosphorylation of p53, nuclear localization of p53, and the transcriptional activity of p53. Stimuli that promote deacetylation of K373, such as was observed in cells treated with the DNA monoalkylating agent adozelesin, can trigger a cell survival response, whereas those that promote K373 acetylation, such as bizelesin or etopside, trigger a cell death response.
C. D. Knights, J. Catania, S. Di Giovanni, S. Muratoglu, R. Perez, A. Swartzbeck, A. A. Quong, X. Zhang, T. Beerman, R. G. Pestell, M. L. Avantaggiati, Distinct p53 acetylation cassettes differentially influence gene-expression patterns and cell fate. J. Cell Biol. 173, 533-544 (2006). [Abstract] [Full Text]
Citation: p53's Posttranslational Code. Sci. STKE 2006, tw180 (2006).
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