title: p53 and MDM2 are regulated by PI-3-kinases on multiple levels under stress induced by UV radiation and proteasome dysfunction.
abstract: p53 is a key stress responsive cellular component. It is negatively regulated by MDM2, which is also its transcriptional target. Here we have studied the involvement of phosphatidylinositol-3-kinases (PI-3-kinase) in the regulation of p53-MDM2 pathway following cellular stress induced by UV damage and proteasomal downregulation. We show that p53 stabilized both by proteasome inhibition and UV damage is transcriptionally active. However, p53 in proteasomally downregulated cells differs from UV-stabilized p53 in its interaction with MDM2, posttranslational modifications and subnuclear localization. It is known that members of PI-3-kinase family are able to directly phosphorylate p53 and MDM2. We show that these kinases regulate p53 accumulation after UV radiation, but accumulation of MDM2 after proteasome inhibition. Both proteins have earlier been shown to translocate into nucleoli after downregulation of the proteasome. We found this effect to be dependent on PI-3-kinase activity but not on any suggested PI-3-kinase phosphorylation site on MDM2. In conclusion, we show here that PI-3-kinases regulate p53-MDM2 pathway on multiple, earlier unknown levels.
authors.affiliation: Department of Virology, Haartman Institute, University of Helsinki and Helsinki University Central Hospital, PO Box 63, FIN-00014 Helsinki, Finland.
authors.forename: Leena
authors.initials: L
authors.lastname: Latonen
authors.forename: Sari
authors.initials: S
authors.lastname: Kurki
authors.forename: Kimmo
authors.initials: K
authors.lastname: Pitkänen
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
mesh_terms: D000818:Animals; D002460:Cell Line; D002466:Cell Nucleolus / Q000378:metabolism; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003546:Cysteine Endopeptidases / Q000502:physiology*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000502:physiology*; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D002867:Chromones; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D007976:Leupeptins; D009025:Morpholines; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D046988:Proteasome Endopeptidase Complex; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde