Department of Biochemistry and Molecular Pharmacology; RNA Therapeutics Institute
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
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.
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. Paper 163.