title: Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.
abstract: Nucleophosmin (NPM) is an important nucleolar phosphoprotein with pleiotropic functions in various cellular processes. In this study, we have further examined the largely uncharacterized role of NPM in transcriptional regulation by uncovering novel NPM-binding transcriptional factors. Among potential interactors, we found that activating protein transcription factor 2 (AP2)alpha forms a complex with NPM during retinoic-acid-induced cell differentiation. We show that this complex is recruited to the promoters of certain retinoic-acid-responsive genes, including NPM itself. Such binding of AP2alpha, and consequent recruitment of NPM, is selective and dependent on a consensus AP2alpha-binding sequence. Remarkably, suppression of NPM by RNA interference alleviates the repression of gene expression mediated by retinoic acid and AP2alpha. Our findings further show that, on promoter binding, NPM probably exerts its repressive effect by inducing a change in local chromatin structure that also engages histone deacetylases. This study unveils a hitherto unrecognized transcriptional corepressor function of the NPM protein, and highlights a novel mechanism by which NPM regulates cell growth and differentiation.
authors.affiliation: Cancer Biochemistry Laboratory, Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan 333, Taiwan, Republic of China.
authors.forename: Hsuan
authors.initials: H
authors.lastname: Liu
authors.forename: Bertrand Chin-Ming
authors.initials: BC
authors.lastname: Tan
authors.forename: Kai Hung
authors.initials: KH
authors.lastname: Tseng
authors.forename: Ching Ping
authors.initials: CP
authors.lastname: Chuang
authors.forename: Chun-Wei
authors.initials: CW
authors.lastname: Yeh
authors.forename: Kwang-Den
authors.initials: KD
authors.lastname: Chen
authors.forename: Sheng-Chung
authors.initials: SC
authors.lastname: Lee
authors.forename: Benjamin Yat-Ming
authors.initials: BY
authors.lastname: Yung
mesh_terms: D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000090243:Nucleophosmin; D011401:Promoter Regions, Genetic / Q000187:drug effects; D025941:Protein Interaction Mapping; D012097:Repressor Proteins / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology
chemical_list: C000716967:NPM1 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; D050656:Transcription Factor AP-2; D000090243:Nucleophosmin; D014212:Tretinoin; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases