URI is an oncogene amplified in ovarian cancer cells and is required for their survival

Jean-Philippe Theurillat; Stefan Christian Metzler; Nico Henzi; Nabil Djouder; Marianne Helbling; Anna-Kathrin Zimmermann; Francis Jacob; Alex Soltermann; Rosmarie Caduff; Viola Heinzelmann-Schwarz; Holger Moch; Wilhelm Krek

doi:10.1016/j.ccr.2011.01.019

URI is an oncogene amplified in ovarian cancer cells and is required for their survival

Cancer Cell. 2011 Mar 8;19(3):317-32. doi: 10.1016/j.ccr.2011.01.019.

Authors

Jean-Philippe Theurillat¹, Stefan Christian Metzler, Nico Henzi, Nabil Djouder, Marianne Helbling, Anna-Kathrin Zimmermann, Francis Jacob, Alex Soltermann, Rosmarie Caduff, Viola Heinzelmann-Schwarz, Holger Moch, Wilhelm Krek

Affiliation

¹ Institute of Cell Biology, ETH Zurich, 8093 Zurich, Switzerland.

PMID: 21397856
DOI: 10.1016/j.ccr.2011.01.019

Abstract

Abrogation of negative feedback control represents a fundamental requirement for aberrantly activated signaling pathways to promote malignant transformation and resistance to therapy. Here we identify URI, which encodes a mitochondrial inhibitor of PP1γ and PP1γ-mediated feedback inhibition of S6K1-BAD survival signaling, as an oncogene amplified and overexpressed in ovarian cancer cell lines and human ovarian carcinomas. URI is an "addicting" oncogene selectively required for the survival of ovarian cancer cells with increased URI copy number. By constitutively detaining PP1γ in inactive complexes, URI sustains S6K1 survival signaling under growth factor-limiting conditions and mediates resistance of cells to cisplatin. Thus, oncogenic activation of URI defines an important mechanism for activating mitochondrial S6K1-BAD signaling and promoting cell survival through disabling PP1γ-dependent negative feedback inhibition.

Publication types

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

MeSH terms

Animals
Cell Line, Tumor
Cell Survival / genetics
Female
Gene Amplification*
Gene Expression Regulation, Neoplastic
HeLa Cells
Humans
Immunoblotting
Immunohistochemistry
In Situ Hybridization, Fluorescence
Intracellular Signaling Peptides and Proteins / genetics*
Intracellular Signaling Peptides and Proteins / metabolism
Kaplan-Meier Estimate
Mice
Mice, Nude
Neoplasms, Experimental / genetics
Neoplasms, Experimental / metabolism
Neoplasms, Experimental / pathology
Oncogene Proteins / genetics*
Oncogene Proteins / metabolism
Ovarian Neoplasms / genetics*
Ovarian Neoplasms / metabolism
Ovarian Neoplasms / pathology
Protein Binding
Protein Phosphatase 1 / metabolism
RNA Interference
Repressor Proteins
Ribosomal Protein S6 Kinases / metabolism
Transplantation, Heterologous
Tumor Burden / genetics
bcl-Associated Death Protein / metabolism

Substances

BAD protein, human
Intracellular Signaling Peptides and Proteins
Oncogene Proteins
Repressor Proteins
URI1 protein, human
bcl-Associated Death Protein
Ribosomal Protein S6 Kinases
Protein Phosphatase 1