A genetic screen for candidate tumor suppressors identifies REST

Thomas F. Westbrook, Eric S. Martin, Michael R. Schlabach, Yumei Leng, Anthony C. Liang, Bin Feng, Jean J. Zhao, Thomas M. Roberts, Gail Mandel, Gregory J. Hannon, Ronald A. DePinho, Lynda Chin, Stephen J. Elledge

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395 Scopus citations

Abstract

Tumorigenesis is a multistep process characterized by a myriad of genetic and epigenetic alterations. Identifying the causal perturbations that confer malignant transformation is a central goal in cancer biology. Here we report an RNAi-based genetic screen for genes that suppress transformation of human mammary epithelial cells. We identified genes previously implicated in proliferative control and epithelial cell function including two established tumor suppressors, TGFBR2 and PTEN. In addition, we uncovered a previously unrecognized tumor suppressor role for REST/NRSF, a transcriptional repressor of neuronal gene expression. Array-CGH analysis identified REST as a frequent target of deletion in colorectal cancer. Furthermore, we detect a frameshift mutation of the REST gene in colorectal cancer cells that encodes a dominantly acting truncation capable of transforming epithelial cells. Cells lacking REST exhibit increased PI(3)K signaling and are dependent upon this pathway for their transformed phenotype. These results implicate REST as a human tumor suppressor and provide a novel approach to identifying candidate genes that suppress the development of human cancer.

Original languageEnglish (US)
Pages (from-to)837-848
Number of pages12
JournalCell
Volume121
Issue number6
DOIs
StatePublished - Jun 17 2005

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Westbrook, T. F., Martin, E. S., Schlabach, M. R., Leng, Y., Liang, A. C., Feng, B., Zhao, J. J., Roberts, T. M., Mandel, G., Hannon, G. J., DePinho, R. A., Chin, L., & Elledge, S. J. (2005). A genetic screen for candidate tumor suppressors identifies REST. Cell, 121(6), 837-848. https://doi.org/10.1016/j.cell.2005.03.033