title: PI3K/Akt-mediated regulation of p53 in cancer.
abstract: Mutations activating the PI3K (phosphoinositide 3-kinase)/Akt signalling pathway and inactivating the TP53 tumour-suppressor gene are common mechanisms that cancer cells require to proliferate and escape pre-programmed cell death. In a well-described mechanism, Akt mediates negative control of p53 levels through enhancing MDM2 (murine double minute 2)-mediated targeting of p53 for degradation. Accumulating evidence is beginning to suggest that, in certain circumstances, PTEN (phosphatase and tensin homologue deleted on chromosome 10)/PI3K/Akt also promotes p53 translation and protein stability, suggesting that additional mechanisms may be involved in the Akt-mediated regulation of p53 in tumours. In the present article, we discuss these aspects in the light of clinical PI3K/Akt inhibitors, where information regarding the effect on p53 activity will be a crucial factor that will undoubtedly influence therapeutic efficacy.
authors.affiliation: *Cancer Research UK/MRC Oxford Institute, Gray Laboratories, Department of Oncology, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Aswin G
authors.initials: AG
authors.lastname: Abraham
authors.affiliation: *Cancer Research UK/MRC Oxford Institute, Gray Laboratories, Department of Oncology, University of Oxford, Old Road Campus, Roosevelt Drive, Oxford OX3 7DQ, U.K.
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
mesh_terms: D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human