Contrasting Effects of Prenyltransferase Inhibitors on Estrogen-Dependent Cell Cycle Progression and Estrogen Receptor-Mediated Transcriptional Activity in MCF-7 Cells

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...

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Published in:Endocrinology (Philadelphia) 2003-03, Vol.144 (3), p.989-998
Main Authors: Doisneau-Sixou, Sophie F, Cestac, Philippe, Chouini, Sarah, Carroll, Jason S, Hamilton, Andrew D, Sebti, Said M, Poirot, Marc, Balaguer, Patrick, Faye, Jean-Charles, Sutherland, Robert L, Favre, Gilles
Format: Article
Language:English
Subjects:
Alkyl and Aryl Transferases
Alkyl and Aryl Transferases - antagonists & inhibitors
Alkyl and Aryl Transferases - physiology
Benzamides
Benzamides - pharmacology
Biological and medical sciences
Breast Neoplasms
Cell Cycle
Cell Cycle - drug effects
Cell Division
Cell Division - drug effects
Cyclin D1
Cyclin D1 - genetics
Dimethylallyltranstransferase
Dimethylallyltranstransferase - antagonists & inhibitors
Enzyme Inhibitors
Enzyme Inhibitors - pharmacology
Estradiol
Estradiol - pharmacology
Estrogen Antagonists
Estrogen Antagonists - pharmacology
Estrogen Receptor alpha
Farnesyltranstransferase
Fundamental and applied biological sciences. Psychology
Gene Expression
Gene Expression - drug effects
Humans
Life Sciences
Methionine - analogs & derivatives
Methionine - pharmacology
Pharmaceutical sciences
Proto-Oncogene Proteins c-myc - genetics
Receptors, Estrogen - genetics
Receptors, Estrogen - physiology
Receptors, Progesterone - genetics
Response Elements
RNA, Messenger - analysis
Transcription, Genetic
Tumor Cells, Cultured
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Summary: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.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2002-220726