TY - JOUR
T1 - Contrasting effects of prenyltransferase inhibitors on estrogen-dependent cell cycle progression and estrogen receptor-mediated transcriptional activity in MCF-7 cells
AU - Doisneau-Sixou, Sophie F.
AU - Cestac, Philippe
AU - Chouini, Sarah
AU - Carroll, Jason S.
AU - Hamilton, Andrew D.
AU - Sebti, Said M.
AU - Poirot, Marc
AU - Balaguer, Patrick
AU - Faye, Jean Charles
AU - Sutherland, Robert L.
AU - Favre, Gilles
PY - 2003/3/1
Y1 - 2003/3/1
N2 - 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.
AB - 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.
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U2 - 10.1210/en.2002-220726
DO - 10.1210/en.2002-220726
M3 - Article
C2 - 12586776
AN - SCOPUS:0037370526
SN - 0013-7227
VL - 144
SP - 989
EP - 998
JO - Endocrinology
JF - Endocrinology
IS - 3
ER -