Abstract |
We studied the effects of 2-methoxyestradiol (2-ME2) and 16alpha-hydroxyestrone (16alpha-OHE1), two metabolites of estradiol (E2), on DNA synthesis, cell cycle progression and cyclin D1 protein levels in estrogen receptor-positive MCF-7 cells. E2 and 16alpha-OHE1 stimulated DNA synthesis, and 2-ME2 inhibited the stimulatory effects of these agents. E2 and 16alpha-OHE1 stimulated the progression of cells from G1 to S phase and this effect was attenuated by 2-ME2. Western blot analysis showed that E2 and 16alpha-OHE1 increased cyclin D1 protein level by about fourfold compared with control. 2-ME2 had no significant effect on cyclin D1; however, it prevented the accumulation of cyclin D1 in the presence of E2 and 16alpha-OHE1. Cells transfected with a cyclin D1 reporter gene and treated with E2 or 16alpha-OHE1 showed 7- and 9.5-fold increase respectively in promoter activity compared with control. This activity was significantly inhibited by 2-ME2. Cyclin D1 transactivation was mediated by the cAMP response element (CRE) region, which binds activating transcription factor 2 (ATF-2). DNA affinity assay showed 2.5- and 3.5-fold increases in ATF-2 binding to CRE in the presence of E2 and 16alpha-OHE1 respectively. The binding of ATF-2 was inhibited by the presence of 2-ME2. These results show that 2-ME2 can downregulate cyclin D1 and thereby cell cycle progression by a mechanism involving the disruption of ATF-2 binding to cyclin D1 promoter.
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Authors | Joan S Lewis, T J Thomas, Richard G Pestell, Chris Albanese, Michael A Gallo, Thresia Thomas |
Journal | Journal of molecular endocrinology
(J Mol Endocrinol)
Vol. 34
Issue 1
Pg. 91-105
(Feb 2005)
ISSN: 0952-5041 [Print] England |
PMID | 15691880
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- ATF2 protein, human
- Activating Transcription Factor 2
- Cyclic AMP Response Element-Binding Protein
- Hydroxyestrones
- Transcription Factors
- Cyclin D1
- 16-hydroxyestrone
- Estradiol
- 2-Methoxyestradiol
- p38 Mitogen-Activated Protein Kinases
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Topics |
- 2-Methoxyestradiol
- Activating Transcription Factor 2
- Blotting, Western
- Breast Neoplasms
(genetics, metabolism)
- Cyclic AMP Response Element-Binding Protein
(metabolism)
- Cyclin D1
(drug effects, metabolism)
- DNA Replication
(drug effects)
- Enzyme Activation
(drug effects)
- Estradiol
(analogs & derivatives, pharmacology)
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Hydroxyestrones
(pharmacology)
- Transcription Factors
(metabolism)
- p38 Mitogen-Activated Protein Kinases
(metabolism)
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