title: Regulation of Neuronal Survival by Nucleophosmin 1 (NPM1) Is Dependent on Its Expression Level, Subcellular Localization, and Oligomerization Status.
abstract: NPM1 (nucleophosmin 1) is a nucleolar phosphoprotein that regulates many cellular processes, including ribosome biogenesis, proliferation, and genomic integrity. Although its role in proliferating cell types and tissues has been extensively investigated, little is known about its function in neurons and in the brain where it is highly expressed. We report that NPM1 protein expression is increased selectively in the striatum in both the R6/2 transgenic and 3-nitropropionic acid-injected mouse models of Huntington's disease. Examination of the effect of ectopic expression on cultured neurons revealed that increasing NPM1 is toxic to otherwise healthy cerebellar granule and cortical neurons. Toxicity is dependent on its cytoplasmic localization and oligomerization status. Forced retention of NPM1 in the nucleus, as well as inhibiting its ability to oligomerize, not only neutralizes NPM1 toxicity but also renders it protective against apoptosis. Although not blocked by pharmacological inhibition of the pro-apoptotic molecules, JNK, glycogen synthase kinase 3 beta, or caspases, toxicity is blocked by compounds targeting cyclin-dependent kinases (CDKs), as well as by dominant-negative forms of CDK1 and CDK2 and the pan-CDK inhibitor, p21(Cip1/Waf1) Although induced in in vivo Huntington's disease models, NPM1 protein levels are unchanged in cultured cerebellar granule and cortical neurons induced to die by low potassium or homocysteic acid treatment, respectively. Moreover, and counterintuitively, knockdown of its expression or inhibition of endogenous NPM1 oligomerization in these cultured neurons is toxic. Taken together, our study suggests that although neurons need NPM1 for survival, an increase in its expression beyond physiological levels and its translocation to the cytoplasm leads to death through abortive cell cycle induction.
authors: From the Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, Texas 75080 and.
authors: Jason A
authors: JA
authors: Pfister
authors: Department of Biological Sciences, Southern Methodist University, Dallas, Texas 75275 sdmello@smu.edu.
authors: Santosh R
authors: SR
authors: D'Mello
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase; D002453:Cell Cycle; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000235:genetics; D000090243:Nucleophosmin; D055503:Protein Multimerization; D051381:Rats; D017208:Rats, Wistar
chemical_list: C493957:Cdkn1a protein, mouse; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C000715570:Npm1 protein, mouse; C000715571:Npm1 protein, rat; D009687:Nuclear Proteins; D000090243:Nucleophosmin; D016203:CDC2 Protein Kinase; C548796:Cdk1 protein, rat; C495893:Cdk2 protein, mouse; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases
keywords: Huntington's disease; cell cycle; cell death; neurodegeneration; neuron; neuronal death; neuronal survival; neuroprotection; nucleophosmin