Nucleoporin Nup155 is part of the p53 network in liver cancer

Kerstin Holzer; Alessandro Ori; Amy Cooke; Daniel Dauch; Elisabeth Drucker; Philip Riemenschneider; Amparo Andres-Pons; Amanda L DiGuilio; Marie-Therese Mackmull; Jochen Baßler; Stephanie Roessler; Kai Breuhahn; Lars Zender; Joseph S Glavy; Frank Dombrowski; Ed Hurt; Peter Schirmacher; Martin Beck; Stephan Singer

doi:10.1038/s41467-019-10133-z

Nucleoporin Nup155 is part of the p53 network in liver cancer

Nat Commun. 2019 May 14;10(1):2147. doi: 10.1038/s41467-019-10133-z.

Authors

Kerstin Holzer^{1

2}, Alessandro Ori^{3

4}, Amy Cooke⁵, Daniel Dauch^{6

7}, Elisabeth Drucker¹, Philip Riemenschneider², Amparo Andres-Pons^{4

8}, Amanda L DiGuilio^{9

10}, Marie-Therese Mackmull⁴, Jochen Baßler¹¹, Stephanie Roessler¹, Kai Breuhahn¹, Lars Zender^{6

7}, Joseph S Glavy^{9

12}, Frank Dombrowski², Ed Hurt¹¹, Peter Schirmacher¹, Martin Beck^{4

13}, Stephan Singer^{14

15

16}

Affiliations

¹ Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany.
² Institute of Pathology, University Medicine Greifswald, 17475, Greifswald, Germany.
³ Leibniz-Institute on Aging, Fritz-Lipmann-Institute (FLI), 07745, Jena, Germany.
⁴ European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117, Heidelberg, Germany.
⁵ European Molecular Biology Laboratory, Directors' Research Unit, 69117, Heidelberg, Germany.
⁶ Department of Internal Medicine VIII, University Hospital Tuebingen, 72076, Tuebingen, Germany.
⁷ Translational Gastrointestinal Oncology Group, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
⁸ Friedrich Miescher Institute for Biomedical Research, 4058, Basel, Switzerland.
⁹ Department of Chemistry, Chemical Biology and Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ, 07030, USA.
¹⁰ Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL, 60637, USA.
¹¹ Heidelberg University Biochemistry Center, 69120, Heidelberg, Germany.
¹² Department of Pharmaceutical Sciences, Ben and Maytee Fisch College of Pharmacy, University of Texas at Tyler, Tyler, TX, 75799, USA.
¹³ Max Planck Institute of Biophysics, 60438, Frankfurt am Main, Germany.
¹⁴ Institute of Pathology, University Hospital Heidelberg, 69120, Heidelberg, Germany. stephan.singer@uni-greifswald.de.
¹⁵ Institute of Pathology, University Medicine Greifswald, 17475, Greifswald, Germany. stephan.singer@uni-greifswald.de.
¹⁶ European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117, Heidelberg, Germany. stephan.singer@uni-greifswald.de.

Abstract

Cancer-relevant signalling pathways rely on bidirectional nucleocytoplasmic transport events through the nuclear pore complex (NPC). However, mechanisms by which individual NPC components (Nups) participate in the regulation of these pathways remain poorly understood. We discover by integrating large scale proteomics, polysome fractionation and a focused RNAi approach that Nup155 controls mRNA translation of p21 (CDKN1A), a key mediator of the p53 response. The underlying mechanism involves transcriptional regulation of the putative tRNA and rRNA methyltransferase FTSJ1 by Nup155. Furthermore, we observe that Nup155 and FTSJ1 are p53 repression targets and accordingly find a correlation between the p53 status, Nup155 and FTSJ1 expression in murine and human hepatocellular carcinoma. Our data suggest an unanticipated regulatory network linking translational control by and repression of a structural NPC component modulating the p53 pathway through its effectors.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / pathology*
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21 / genetics*
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Datasets as Topic
Gene Expression Regulation, Neoplastic
Humans
Liver Neoplasms / genetics
Liver Neoplasms / pathology*
Liver Neoplasms, Experimental / genetics
Liver Neoplasms, Experimental / pathology
Methyltransferases / genetics*
Methyltransferases / metabolism
Mice
Nuclear Pore Complex Proteins / genetics
Nuclear Pore Complex Proteins / metabolism*
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism
RNA, Small Interfering / metabolism
Tumor Suppressor Protein p53 / metabolism*

Substances

CDKN1A protein, human
Cyclin-Dependent Kinase Inhibitor p21
NUP155 protein, human
NUP155 protein, mouse
Nuclear Pore Complex Proteins
Nuclear Proteins
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
FTSJ1 protein, human
Methyltransferases

Abstract

Publication types

MeSH terms

Substances

Grants and funding