Department of Biochemistry and Molecular Pharmacology; RNA Therapeutics Institute
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
Biochemistry | Biochemistry, Biophysics, and Structural Biology | Cancer Biology | Cell Biology | Molecular Biology | Molecular Genetics
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.
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DOI of Published Version
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
Singer, Stephan; Zhao, Ruiying; Barsotti, Anthony M.; Ouwehand, Anette; Fazollahi, Mina; Coutavas, Elias; Breuhahn, Kai; Neumann, Olaf; Longerich, Thomas; Pusterla, Tobias; Powers, Maureen A.; Giles, Keith M.; Leedman, Peter J.; Hess, Jochen; Grunwald, David; Bussemaker, Harmen J.; Singer, Robert H.; Schirmacher, Peter; and Prives, Carol, "Nuclear pore component Nup98 is a potential tumor suppressor and regulates posttranscriptional expression of select p53 target genes" (2012). Biochemistry and Molecular Pharmacology Publications and Presentations. 163.