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Mol. Cell. Biol. 24 (12): 5548-5564

Copyright © 2004 by the American Society for Microbiology. All rights reserved.

The ETS Transcription Factor ESE-1 Transforms MCF-12A Human Mammary Epithelial Cells via a Novel Cytoplasmic Mechanism

Jason D. Prescott,1,2* Karen S. N. Koto,3 Meenakshi Singh,4 and Arthur Gutierrez-Hartmann1,2,5,6*

Departments of Medicine,5 Pathology,4 Biochemistry and Molecular Genetics,6 Medical Scientist Training Program,1 Program in Molecular Biology, University of Colorado Health Sciences Center, Denver, Colorado,2 Department of Biology, Oberlin College, Oberlin, Ohio3

Received for publication 19 November 2003. Revision received 18 December 2003. Accepted for publication 12 March 2004.

Abstract: Several different transcription factors, including estrogen receptor, progesterone receptor, and ETS family members, have been implicated in human breast cancer, indicating that transcription factor-induced alterations in gene expression underlie mammary cell transformation. ESE-1 is an epithelium-specific ETS transcription factor that contains two distinguishing domains, a serine- and aspartic acid-rich (SAR) domain and an AT hook domain. ESE-1 is abundantly expressed in human breast cancer and trans-activates epithelium-specific gene promoters in transient transfection assays. While it has been presumed that ETS factors transform mammary epithelial cells via their nuclear transcriptional functions, here we show (i) that ESE-1 protein is cytoplasmic in human breast cancer cells; (ii) that stably expressed green fluorescent protein-ESE-1 transforms MCF-12A human mammary epithelial cells; and (iii) that the ESE-1 SAR domain, acting in the cytoplasm, is necessary and sufficient to mediate this transformation. Deletion of transcriptional regulatory or nuclear localization domains does not impair ESE-1-mediated transformation, whereas fusing the simian virus 40 T-antigen nuclear localization signal to various ESE-1 constructs, including the SAR domain alone, inhibits their transforming capacity. Finally, we show that the nuclear localization of ESE-1 protein induces apoptosis in nontransformed mammary epithelial cells via a transcription-dependent mechanism. Together, our studies reveal two distinct ESE-1 functions, apoptosis and transformation, where the ESE-1 transcription activation domain contributes to apoptosis and the SAR domain mediates transformation via a novel nonnuclear, nontranscriptional mechanism. These studies not only describe a unique ETS factor transformation mechanism but also establish a new paradigm for cell transformation in general.

* Corresponding author. Mailing address: University of Colorado Health Sciences Center, 4200 East Ninth Ave., Box B-151, Denver, CO 80262. Phone: (303) 315-8443. Fax: (303) 315-4525. E-mail for Jason D. Prescott: jason.prescott{at}uchsc.edu. E-mail for Arthur Gutierrez-Hartmann: a.gutierrez-hartmann{at}uchsc.edu.

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