Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells

Sophie F. Doisneau-Sixou, Philippe Cestac, Sarah Chouini, Jason S. Carroll, Andrew D. Hamilton, Said M. Sebti, Marc Poirot, Patrick Balaguer, Jean Charles Faye, Robert L. Sutherland, Gilles Favre

Research output: Contribution to journalArticle

Abstract

Activation of estrogen receptors (ERs) by estrogens triggers both ER nuclear transcriptional activity and Src/Ras/Erks pathway-dependent mitogenic activity. The present study implicates prenylated proteins in both estrogenic actions. The farnesyltransferase and geranylgeranyltransferase I inhibitors (FTI-277 and GGTI-298, respectively) antagonize estradiol-stimulated cell cycle progression, progesterone receptor, cyclin D1, and c-Myc expression. In contrast, the inhibitors markedly stimulate transcription from two genes containing estrogen response elements, both in the absence and presence of estradiol. The pure antiestrogen ICI 182,780 inhibits by more than 85% these effects on transcription. We demonstrate that both FTI-277 and GGTI-298 increase the association of steroid receptor coactivator-1 with ERα and FTI-277 decreases the association of ERα with the histone deacetylase 1, a known transcriptional repressor. In addition, FTI-277 has no marked effect on the association of the two corepressors, nuclear receptor corepressor and silencing mediator of retinoid and thyroid receptor with ERα, whereas GGTI-298, similar to tamoxifen, clearly increased these associations. Together, these results demonstrate that prenylated proteins play a role in estradiol stimulation of proliferation and progesterone receptor expression. However, they antagonize the ability of ERα to stimulate estrogen response element-dependent transcriptional activity, acting presumably through coregulator complex formation.

Original languageEnglish (US)
Pages (from-to)989-998
Number of pages10
JournalEndocrinology
Volume144
Issue number3
DOIs
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Endocrinology

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    Doisneau-Sixou, S. F., Cestac, P., Chouini, S., Carroll, J. S., Hamilton, A. D., Sebti, S. M., Poirot, M., Balaguer, P., Faye, J. C., Sutherland, R. L., & Favre, G. (2003). Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells. Endocrinology, 144(3), 989-998. https://doi.org/10.1210/en.2002-220726