Submitted June 6, 2008
Accepted March 6, 2009
NPM-ALK inhibits the p53 tumour suppressor pathway in an MDM2 and JNK-dependent manner
Yu-Xin Cui, Alan Kerby, Fiona Kate Elizabeth McDuff, Hongtao Ye, and Suzanne Dawn Turner*
Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
* Corresponding author; email: sdt36{at}cam.ac.uk.
Anaplastic large cell lymphoma (ALCL) is characterised by the presence of the t(2;5)(p23;q35) generating the Nucleophosmin-Anaplastic Lymphoma Kinase (NPM-ALK) fusion protein, a hyperactive kinase with transforming properties. Among these properties is the ability to regulate activity of the p53 tumour suppressor protein. In many human cancers p53 is inactivated by mutation or other means, in some cases as a result of up-regulation of the negative regulator MDM2. However, the majority of ALK-expressing ALCL carry wild-type p53 and do not over express MDM2. We demonstrate a novel p53-dependent pathogenetic mechanism in ALK-expressing lymphoma. We confirm previously published reports of NPM-ALK-induced activation of the PI 3-Kinase and JNK SAP Kinase proteins but in this study demonstrate a role for these in the regulation of p53 activity in an intricate signalling system. Specifically, constitutive ALK signalling leads to the functional inactivation and/or degradation of p53 in JNK and MDM2 dependent manners. We also show nuclear exclusion of p53 in a PI 3-Kinase dependent manner. Furthermore, we demonstrate that reactivation of p53 in ALK-expressing cells as a result of pharmacological inhibition of JNK, PI 3-Kinase and/or MDM2 activities results in the induction of apoptosis suggesting a novel therapeutic modality.
