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Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes
Biochemistry and Molecular Pharmacology Publications and Presentations
  • Stephan Singer, Columbia University
  • Ruiying Zhao, Columbia University
  • Anthony M. Barsotti, Columbia University
  • Anette Ouwehand, Delft University of Technology
  • Mina Fazollahi, Columbia University
  • Elias Coutavas, Rockefeller University
  • Kai Breuhahn, University Hospital Heidelberg
  • Olaf Neumann, University Hospital Heidelberg
  • Thomas Longerich, University Hospital Heidelberg
  • Tobias Pusterla, German Cancer Research Center
  • Maureen A. Powers, Emory University
  • Keith M. Giles, University of Western Australia
  • Peter J. Leedman, University of Western Australia
  • Jochen Hess, German Cancer Research Center
  • David Grunwald, University of Massachusetts Medical School
  • Harmen J. Bussemaker, Columbia University
  • Robert H. Singer, Albert Einstein College of Medicine
  • Peter Schirmacher, University Hospital Heidelberg
  • Carol Prives, Columbia University
UMMS Affiliation
Department of Biochemistry and Molecular Pharmacology; RNA Therapeutics Institute
Date
12-14-2012
Document Type
Article
Medical Subject Headings
14-3-3 Proteins; 3' Untranslated Regions; Animals; Antineoplastic Agents, Phytogenic; Apoptosis; Binding Sites; Camptothecin; Carcinoma, Hepatocellular; Cell Aging; Cyclin-Dependent Kinase Inhibitor p21; Exosomes; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Liver Neoplasms; Male; Mice; Mice, Knockout; Nuclear Pore Complex Proteins; P-Glycoproteins; RNA Interference; *RNA Processing, Post-Transcriptional; RNA Stability; RNA, Messenger; Time Factors; Transfection; Tumor Suppressor Protein p53
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 (14-3-3sigma) 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.
Comments

Citation: Singer S, Zhao R, Barsotti AM, Ouwehand A, Fazollahi M, Coutavas E, Breuhahn K, Neumann O, Longerich T, Pusterla T, Powers MA, Giles KM, Leedman PJ, Hess J, Grunwald D, Bussemaker HJ, Singer RH, Schirmacher P, Prives C. Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes. Mol Cell. 2012 Dec 14;48(5):799-810. doi:10.1016/j.molcel.2012.09.020. Link to article on publisher's site

Publisher pdf posted as allowed by Elsevier user licence at http://www.elsevier.com/about/open-access/open-access-policies/oa-license-policy/elsevier-user-license.

At the time of publication, David Grünwald was not yet affiliated with the University of Massachusetts Medical School.

Related Resources
Link to Article in PubMed
PubMed ID
23102701
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Citation Information
Stephan Singer, Ruiying Zhao, Anthony M. Barsotti, Anette Ouwehand, et al.. "Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes" Vol. 48 Iss. 5 (2012) ISSN: 1097-2765 (Linking)
Available at: http://works.bepress.com/david_grunwald/1/