Editors' ChoiceCancer

Nucleus Not Needed for ETS Factor

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Science's STKE  08 Jun 2004:
Vol. 2004, Issue 236, pp. tw209
DOI: 10.1126/stke.2362004tw209

The ETS transcription factors, which can either activate or repress gene expression, have been implicated in tumorigenesis. The epithelium-specific family member called ESE-1 regulates cell differentiation, and its overexpression has been associated with breast cancer progression. Although ESE-1 has been shown to activate transcription of reporter genes when transiently expressed in cells, Prescott et al. propose that ESE-1 may exert its transforming effects in the cytoplasm rather than in the nucleus. Deletion analysis revealed that an internal region that is rich in serine and aspartic acid residues (SAR domain) is necessary and sufficient to induce the transformation of human mammary epithelial cells. Endogenous ESE-1 protein was detected in the cytoplasm of breast cancer tissues and in breast cancer cell lines. In contrast, transiently expressed ESE-1 localized in the nucleus of human mammary epithelial cells and specifically induced apoptosis. Deletion of the ESE-1 transactivation domain impaired this effect, which indicated that its transcription factor function contributes to ESE-1-mediated apoptosis. However, deletion of the transcription regulatory domain did not affect ESE-1-induced transformation. Overexpressed SAR domain localized to both the cytoplasm and nucleus and promoted anchorage-independent growth of epithelial cells. Appending a viral nuclear localization signal to the SAR domain enforced strict nuclear localization of SAR and blocked its ability to transform cells. The authors propose that nuclear apoptotic function of the ESE-1 transcription activity may be regulated by a mechanism that retains the transcription factor in the cytoplasm and that the SAR domain mediates transformation by a nonnuclear, nontranscriptional mechanism. Interestingly, the SAR domain is absent from all other ETS proteins.

J. D. Prescott, K. S. N. Koto, M. Singh, A. Gutierrez-Hartmann, The ETS transcription factor ESE-1 transforms MCF-12A human mammary epithelial cells via a novel cytoplasmic mechanism. Mol. Cell. Biol. 24, 5548-5564 (2004). [Abstract] [Full Text]

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