title: The p53/mouse double minute 2 homolog complex deregulation in merlin-deficient tumours.
abstract: Deficiency of the tumour suppressor merlin leads to the development of schwannomas, meningiomas and ependymomas occurring spontaneously or as a part of the hereditary disease Neurofibromatosis type 2 (NF2). Merlin loss is also found in a proportion of other cancers like mesothelioma, melanoma, breast cancer and glioblastoma. The tumour suppressor/transcription factor p53 regulates proliferation, survival and differentiation and its deficiency plays a role in the development of many tumours. 53 can be negatively regulated by FAK, PI3K/AKT and MDM2 and possibly positively regulated by merlin in different cell lines. In this study we investigated the role of p53 in merlin-deficient tumours. Using our in vitro model of primary human schwannoma cells we have previously demonstrated that FAK is overexpressed/activated and localises into the nucleus of schwannoma cells increasing proliferation. AKT is strongly activated via platelet-derived growth factor (PDGF) - and insulin-like growth factor 1 (IGF1) - receptors increasing survival. Here we investigated p53 regulation and its role in proliferation and survival of human primary schwannoma cells using western blotting, immunocytochemistry, immunohistochemistry and proliferation, survival and transcription factor assays. In human primary schwannoma cells p53 was found to be downregulated while MDM2 was upregulated leading to increased cell proliferation and survival. p53 is regulated by merlin involving FAK, AKT and MDM2. Merlin reintroduction into schwannoma cells increased p53 levels and activity, and treatment with Nutlin-3, a drug which increases p53 stability by disrupting the p53/MDM2 complex, decreased tumour growth and reduced cell survival. These findings are important to dissect the mechanisms responsible for the development of merlin-deficient tumours and to identify new therapeutic targets. We suggest that Nutlin-3, possibly in combination with FAK or PI3K inhibitors, can be employed as a novel treatment for schwannoma and other merlin-deficient tumours.
authors.affiliation: Plymouth University, Peninsula Schools of Medicine and Dentistry, The Institute of Translational and Stratified Medicine, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
authors.forename: Sylwia
authors.initials: S
authors.lastname: Ammoun
authors.affiliation: Plymouth University, Peninsula Schools of Medicine and Dentistry, The Institute of Translational and Stratified Medicine, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
authors.forename: Marei Caroline
authors.initials: MC
authors.lastname: Schmid
authors.affiliation: Plymouth University, Peninsula Schools of Medicine and Dentistry, The Institute of Translational and Stratified Medicine, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Histopathology, Derriford Hospital, Plymouth, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Hilton
authors.affiliation: Plymouth University, Peninsula Schools of Medicine and Dentistry, The Institute of Translational and Stratified Medicine, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Barczyk
authors.affiliation: Plymouth University, Peninsula Schools of Medicine and Dentistry, The Institute of Translational and Stratified Medicine, The John Bull Building, Tamar Science Park, Research Way, Plymouth PL6 8BU, UK. Electronic address: oliver.hanemann@plymouth.ac.uk.
authors.forename: Clemens Oliver
authors.initials: CO
authors.lastname: Hanemann
mesh_terms: D051417:Focal Adhesion Kinase 1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D009442:Neurilemmoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025581:Neurofibromin 2 / Q000172:deficiency*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D025581:Neurofibromin 2; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D051057:Proto-Oncogene Proteins c-akt
keywords: FAK; Merlin; Neurofibromatosis type 2 (NF2); Proliferation and survival; p53/MDM2