NPM-ALK inhibits the p53 tumor suppressor pathway in an MDM2 and JNK-dependent manner.
Anaplastic large cell lymphoma (ALCL) is characterized 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 tumor 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 phosphoinositide (PI) 3-kinase and Jun N-terminal kinase (JNK) stress-activated protein (SAP) kinase proteins, but in this study demonstrate a role for these in the regulation of p53 activity in an intricate signaling system. Specifically, constitutive ALK signaling 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 pharmacologic inhibition of JNK, PI 3-kinase, and/or MDM2 activities results in the induction of apoptosis suggesting a novel therapeutic modality.
Cui
Yu-Xin
YX
Department of Pathology, University of Cambridge, United Kingdom.
Kerby
Alan
A
McDuff
Fiona Kate Elizabeth
FK
Ye
Hongtao
H
Turner
Suzanne Dawn
SD
D017209:Apoptosis; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008223:Lymphoma / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000378:metabolism
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D019869:Phosphatidylinositol 3-Kinases; C107023:p80(NPM-ALK) protein; D011505:Protein-Tyrosine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8