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ICI182,780 induces p21Waf1 gene transcription through releasing histone deacetylase 1 and estrogen receptor alpha from Sp1 sites to induce cell cycle arrest in MCF-7 breast cancer cell line.
- Source :
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The Journal of biological chemistry [J Biol Chem] 2005 Feb 04; Vol. 280 (5), pp. 3185-96. Date of Electronic Publication: 2004 Nov 19. - Publication Year :
- 2005
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Abstract
- We used the estrogen-responsive MCF-7 breast cancer cell line as a relevant model to study the anti-proliferative effects of ICI182,780 and identified the negative cell cycle regulator p21Waf1 as a specific target of ICI182,780. Furthermore, silencing of the p21Waf1 expression by small interfering RNA overcame the G0/G1 cell cycle arrest induced by ICI182,780, suggesting that the induction of p21Waf1 expression has a direct role in mediating the ICI182,780-induced G0/G1 arrest. We further demonstrated that the induction of p21Waf1 by ICI182,780 is mediated at transcriptional and gene promoter levels through the proximal Sp1 sites located near the transcription start site. Co-immunoprecipitation, DNA "pull-down," and chromatin immunoprecipitation experiments together showed that in cycling cells, estrogen receptor alpha and histone deacetylase 1 (HDAC1) are recruited to the proximal Sp1 sites of the promoter to repress p21Waf1 expression. In the presence of ICI182,780, estrogen receptor alpha and HDACs are dissociated from Sp1, resulting in increased histone acetylation and de-repression of the p21Waf1 promoter and induction of p21Waf1 expression. The fact that p21Waf1 expression is normally repressed by HDAC activity in cycling cells is further demonstrated by the finding that p21Waf1 transcription can be induced by the silencing of HDACs with small interfering RNA or treatment with HDAC inhibitors.
- Subjects :
- Binding Sites
Cell Line, Tumor
Cyclin-Dependent Kinase Inhibitor p21
Enzyme Inhibitors pharmacology
Fulvestrant
G1 Phase drug effects
Gene Silencing
Histone Deacetylase Inhibitors
Humans
Hydroxamic Acids pharmacology
Promoter Regions, Genetic physiology
RNA, Small Interfering
Sp1 Transcription Factor metabolism
Transcriptional Activation drug effects
Up-Regulation drug effects
Up-Regulation genetics
Antineoplastic Agents, Hormonal pharmacology
Breast Neoplasms
Cell Cycle Proteins genetics
Estradiol analogs & derivatives
Estradiol pharmacology
Estrogen Receptor alpha metabolism
Histone Deacetylases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 280
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15557281
- Full Text :
- https://doi.org/10.1074/jbc.M408063200