title: Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes.
abstract: The p53 tumor suppressor utilizes multiple mechanisms to selectively regulate its myriad target genes, which in turn mediate diverse cellular processes. Here, using conventional and single-molecule mRNA analyses, we demonstrate that the nucleoporin Nup98 is required for full expression of p21, a key effector of the p53 pathway, but not several other p53 target genes. Nup98 regulates p21 mRNA levels by a posttranscriptional mechanism in which a complex containing Nup98 and the p21 mRNA 3'UTR protects p21 mRNA from degradation by the exosome. An in silico approach revealed another p53 target (14-3-3σ) to be similarly regulated by Nup98. The expression of Nup98 is reduced in murine and human hepatocellular carcinomas (HCCs) and correlates with p21 expression in HCC patients. Our study elucidates a previously unrecognized function of wild-type Nup98 in regulating select p53 target genes that is distinct from the well-characterized oncogenic properties of Nup98 fusion proteins.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Stephan
authors.initials: S
authors.lastname: Singer
authors.forename: Ruiying
authors.initials: R
authors.lastname: Zhao
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Barsotti
authors.forename: Anette
authors.initials: A
authors.lastname: Ouwehand
authors.forename: Mina
authors.initials: M
authors.lastname: Fazollahi
authors.forename: Elias
authors.initials: E
authors.lastname: Coutavas
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
authors.forename: Olaf
authors.initials: O
authors.lastname: Neumann
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Tobias
authors.initials: T
authors.lastname: Pusterla
authors.forename: Maureen A
authors.initials: MA
authors.lastname: Powers
authors.forename: Keith M
authors.initials: KM
authors.lastname: Giles
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.forename: David
authors.initials: D
authors.lastname: Grunwald
authors.forename: Harmen J
authors.initials: HJ
authors.lastname: Bussemaker
authors.forename: Robert H
authors.initials: RH
authors.lastname: Singer
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Carol
authors.initials: C
authors.lastname: Prives
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D020413:3' Untranslated Regions; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D002166:Camptothecin / Q000494:pharmacology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D055354:Exosomes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional; D020871:RNA Stability; D012333:RNA, Messenger / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D048948:14-3-3 Proteins; D020413:3' Untranslated Regions; D018435:ATP Binding Cassette Transporter, Subfamily B; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D028861:Nuclear Pore Complex Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C493956:CDKN1A protein, human; C465451:Nup98 protein, human; C495901:TP53 protein, human; C482982:YWHAB protein, human