Nucleophosmin acts as a novel AP2alpha-binding transcriptional corepressor during cell differentiation.
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.
Liu
Hsuan
H
Cancer Biochemistry Laboratory, Department of Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-San, Tao-Yuan 333, Taiwan, Republic of China.
Tan
Bertrand Chin-Ming
BC
Tseng
Kai Hung
KH
Chuang
Ching Ping
CP
Yeh
Chun-Wei
CW
Chen
Kwang-Den
KD
Lee
Sheng-Chung
SC
Yung
Benjamin Yat-Ming
BY
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
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