UMMS Affiliation

Program in Gene Function and Expression; Program in Molecular Medicine; Department of Cell and Developmental Biology; Information Services

Publication Date

12-20-2012

Document Type

Article

Subjects

Genes, p53; RNA Interference; Telomerase; Cell Proliferation; Neoplasms

Disciplines

Cancer Biology | Genetics and Genomics | Molecular Genetics

Abstract

Numerous genetic and epigenetic alterations render cancer cells selectively dependent on specific genes and regulatory pathways, and represent potential vulnerabilities that can be therapeutically exploited. Here we describe an RNA interference (RNAi)-based synthetic interaction screen to identify genes preferentially required for proliferation of p53-deficient (p53-) human cancer cells. We find that compared to p53-competent (p53+) human cancer cell lines, diverse p53- human cancer cell lines are preferentially sensitive to loss of the transcription factor ETV1 and the DNA damage kinase ATR. In p53- cells, RNAi-mediated knockdown of ETV1 or ATR results in decreased expression of the telomerase catalytic subunit TERT leading to growth arrest, which can be reversed by ectopic TERT expression. Chromatin immunoprecipitation analysis reveals that ETV1 binds to a region downstream of the TERT transcriptional start-site in p53- but not p53+ cells. We find that the role of ATR is to phosphorylate and thereby stabilize ETV1. Our collective results identify a regulatory pathway involving ETV1, ATR, and TERT that is preferentially important for proliferation of diverse p53- cancer cells.

Comments

Citation: PLoS Genet. 2012 Dec;8(12):e1003151. doi: 10.1371/journal.pgen.1003151. Link to article on publisher's site

Copyright: © 2012 Xie et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

PLoS genetics

PubMed ID

23284306

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