AKT regulates NPM dependent ARF localization and p53mut stability in tumors
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Garth Hamilton1,*, Aswin G. Abraham1,*, Jennifer Morton2, Oliver Sampson1, Dafni E. Pefani1, Svetlana Khoronenkova1, Anna Grawenda1, Angelos Papaspyropoulos1, Nigel Jamieson3, Colin McKay3, Owen Sansom2, Grigory L. Dianov1 and Eric O’Neill1
1 Cancer Research UK/MRC Oxford Institute, Department of Oncology, University of Oxford, Old Road Campus, Roosevelt Drive, UK
2 Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, UK
3 West of Scotland Pancreatic Unit and University Department of Surgery, Glasgow Royal Infirmary, Alexandra Parade. Glasgow
* These authors contributed equally to this work
Eric. O’Neill , email:
Received: June 23, 2014 Accepted: July 7, 2014 Published: July 8, 2014
Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53mut stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53mut status.
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