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 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

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Dimethylallyltranstransferase
MCF-7 Cells
Estrogen Receptors
Cell Cycle
Estrogens
Estradiol
Co-Repressor Proteins
Response Elements
Progesterone Receptors
Nuclear Receptor Coactivator 1
Histone Deacetylase 1
Farnesyltranstransferase
Estrogen Receptor Modulators
Cyclin D1
Retinoids
Tamoxifen
Thyroid Gland
Proteins
FTI 277

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells. / Doisneau-Sixou, Sophie F.; Cestac, Philippe; Chouini, Sarah; Carroll, Jason S.; Hamilton, Andrew; Sebti, Said M.; Poirot, Marc; Balaguer, Patrick; Faye, Jean Charles; Sutherland, Robert L.; Favre, Gilles.

In: Endocrinology, Vol. 144, No. 3, 01.03.2003, p. 989-998.

Research output: Contribution to journalArticle

Doisneau-Sixou, SF, Cestac, P, Chouini, S, Carroll, JS, Hamilton, A, Sebti, SM, Poirot, M, Balaguer, P, Faye, JC, Sutherland, RL & 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, vol. 144, no. 3, pp. 989-998. https://doi.org/10.1210/en.2002-220726
Doisneau-Sixou, Sophie F. ; Cestac, Philippe ; Chouini, Sarah ; Carroll, Jason S. ; Hamilton, Andrew ; Sebti, Said M. ; Poirot, Marc ; Balaguer, Patrick ; Faye, Jean Charles ; Sutherland, Robert L. ; Favre, Gilles. / Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells. In: Endocrinology. 2003 ; Vol. 144, No. 3. pp. 989-998.
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