title: How phosphorylation controls p53.
abstract: The tumor suppressor p53 is a transcription factor that integrates distinct environmental signals including DNA damage, metabolic stress, oncogene activation, hypoxia and virus infection into a common biological outcome that maintains normal cellular control and tissue integrity. p53 is regulated at the post-translational level by protein-protein interactions and covalent modifications, including phosphorylation at over twenty phosphor-acceptor sites. In this perspective we discuss the function of two evolutionarily conserved p53 phosphorylation motifs, located within the N-terminal transactivation and C-terminal regulatory domains, which have recently been shown to play a tumour suppressive role in stem cell niches. We also consider how mechanisms in addition to phosphorylation by stress-activated kinases can lead to the activation of p53 as a transcription factor, and we review the dual role of p53-activating kinases as tumor suppressors and oncoproteins. Finally, we discuss how changes in the specific activity of p53 can have profound effects not only on cancer development, but also on organism aging.
authors.affiliation: CRUK p53 Signal Transduction Group, Edinburgh Cancer Research Centre, Institute of Genetics and Molecular Medicine, University of Edinburgh, Scotland, UK. nicky.maclaine@ed.ac.uk
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: MacLaine
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D010750:Phosphoproteins; D015534:Trans-Activators; C486419:Trp63 protein, mouse; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D047389:Casein Kinase I; D017346:Protein Serine-Threonine Kinases