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- Title
HES-1 inhibits 17ß-estradiol and heregulin-ß1-mediated upregulation of E2F-1.
- Authors
Hartman, Johan; Müller, Patrick; Foster, James S.; Wimalasena, Jay; Gustafsson, Jan-Åke; Ström, Anders
- Abstract
We have previously shown that expression of the transcription factor HES-1 is required for the growth-inhibitory effect of all-trans retinoic acid on MCF-7 cells. In this study, we have used T47D cells with tetracyclin-regulated expression of wild-type or a dominant-negative form of HES-1. Expression of HES-1 in T47D cells inhibited G1/S-phase transition and activation of Cdk2 elicited by estrogen. Estrogen treatment of T47D cells caused increased expression of E2F-1, and this expression was inhibited by cotreatment with all-trans retinoic acid. We show that the effect is mediated through HES-1, which directly downregulates E2F-1 expression through a CACGAG-site within the E2F-1 promoter. Furthermore, proliferation caused by heregulin-ß1 treatment of T47D cells was inhibited by all-trans retinoic acid and this effect was mediated by HES-1. Interestingly, heregulin-ß1-mediated upregulation of E2F-1 expression was directly inhibited by HES-1 through the same CACGAG-site as seen with estrogen-stimulated induction. In addition, we found that two important downstream target genes of estrogen and heregulin-ß1 that are regulated through E2F-1, cyclin E and NPAT, were both regulated in a similar fashion by all-trans retinoic acid, and these effects were antagonized by dominant-negative HES-1. These findings establish that HES-1 inhibits both estrogen- and heregulin-ß1-stimulated growth of breast cancer cells, and further suggest that growth inhibition induced in these cells by all-trans retinoic acid occurs via HES-1-mediated downregulation of E2F-1 expression.Oncogene (2004) 23, 8826-8833. doi:10.1038/sj.onc.1208139 Published online 4 October 2004
- Subjects
ESTRADIOL; ESTROGEN; TRANSCRIPTION factors; CELLULAR pathology; TRETINOIN; CELLS
- Publication
Oncogene, 2004, Vol 23, Issue 54, p8826
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208139