Smad4 as a Transcription Corepressor for Estrogen Receptor α*

Antiestrogen compounds exhibit a variety of different effects in different tissues and are widely used for the treatment of osteoporosis, breast cancer, and other diseases. Upon examining the molecular mechanisms, we found that Smad4, a common signal transducer in the bone morphogenetic protein (BMP)/transforming growth factor-β (TGF-β) signaling pathway, functions as a transcription corepressor for human estrogen receptor α (ERα). Endogenous ERα was co-immunoprecipitated with Smad4, and the interaction was induced by antiestrogen ligands such as tamoxifen, raloxifene, and droloxifen, which was confirmed in chromatin immunoprecipitation assays. Smad4 and ERα form a complex when ERα binds to the estrogen-responsive element within the estrogen target gene promoter. Importantly, the expression of Smad4 inhibits both antiestrogen-induced luciferase activity and estrogen downstream target gene transcription in breast cancer cells. Mapping of the interaction domains indicates that the activation function 1 (AF1) domain of ERα is essential for its interaction with Smad4, while the MH1 domain and linker region of Smad4 are essential for the interaction. Our findings represent a novel mechanism that TGF-β may regulate cell fate through Smad4-mediated cross-talk with estrogen.

• Publication year

  2003

• Venue

  Journal of Biological Chemistry

• Publication date

  2003-04-25

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1074/JBC.M212332200PMID 12576474
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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• Estrogen receptor interaction with co-activators and co-repressors.

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• Controlling TGF-β signaling

  2000cited by this paper
• Prognostic significance of oestrogen receptor beta in breast cancer.

  2000cited by this paper
• Selective estrogen receptor modulators: structure, function, and clinical use.

  2000cited by this paper
• Prognostic significance of oestrogen receptor β in breast cancer

  2000cited by this paper
• Signaling of transforming growth factor-beta family members through Smad proteins.

  2000cited by this paper
• Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription.

  2000cited by this paper
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  1999cited by this paper
• Increased expression of estrogen receptor beta mRNA in tamoxifen-resistant breast cancer patients.

  1999cited by this paper
• Expression profile of agonistic Smads in human breast cancer cells: Absence of regulation by estrogens

  1999cited by this paper
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  1999cited by this paper
• Regulation of hormone-induced histone hyperacetylation and gene activation via acetylation of an acetylase.

  1999cited by this paper
• Expression of wild-type estrogen receptor beta and variant isoforms in human breast cancer.

  1999cited by this paper
• Nuclear receptor coactivators: multiple enzymes, multiple complexes, multiple functions.

  1999cited by this paper
• Estrogen receptor null mice: what have we learned and where will they lead us?

  1999cited by this paper
• Peptide antagonists of the human estrogen receptor.

  1999cited by this paper
• TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads.

  1998cited by this paper
• Isolation of Estrogen-Responsive Genes with a CpG Island Library

  1998cited by this paper
• Transcriptional Activators of TGF-β Responses: Smads

  1998cited by this paper
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  1998cited by this paper
• TGF-beta signal transduction.

  1998cited by this paper
• Smads: transcriptional activators of TGF-beta responses.

  1998cited by this paper
• TGF-β singaling and cancer: structural and functional consequences of mutations in Smads

  1998cited by this paper
• Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas.

  1998cited by this paper
• The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen.

  1998cited by this paper
• Smad3 mutant mice develop metastatic colorectal cancer.

  1998cited by this paper
• The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT.

  1997cited by this paper
• The role of transforming growth factor-beta in the regulation of estrogen receptor expression in the MCF-7 breast cancer cell line.

  1997cited by this paper
• Heteromeric and homomeric interactions correlate with signaling activity and functional cooperativity of Smad3 and Smad4/DPC4

  1997cited by this paper
• Differential Interaction of Nuclear Receptors with the Putative Human Transcriptional Coactivator hTIF1*

  1997cited by this paper
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  1997cited by this paper
• GRIP1, a transcriptional coactivator for the AF-2 transactivation domain of steroid, thyroid, retinoid, and vitamin D receptors

  1997cited by this paper
• GRIP1, a novel mouse protein that serves as a transcriptional coactivator in yeast for the hormone binding domains of steroid receptors.

  1996cited by this paper
• TIF2, a 160 kDa transcriptional mediator for the ligand‐dependent activation function AF‐2 of nuclear receptors.

  1996cited by this paper
• Defects of TGF-β receptor signaling in mammary cell tumorigenesis

  1996cited by this paper
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  1996cited by this paper
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  1996cited by this paper
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  1996cited by this paper
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  1996cited by this paper
• CREB binding protein acts synergistically with steroid receptor coactivator-1 to enhance steroid receptor-dependent transcription.

  1996cited by this paper
• Defects of TGF-beta receptor signaling in mammary cell tumorigenesis.

  1996cited by this paper
• Partnership between DPC4 and SMAD proteins in TGF-β signalling pathways

  1996cited by this paper
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  1996cited by this paper
• Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor

  1995cited by this paper
• Polarity-specific activities of retinoic acid receptors determined by a co-repressor

  1995cited by this paper
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  1995cited by this paper
• Sequence and Characterization of a Coactivator for the Steroid Hormone Receptor Superfamily

  1995cited by this paper
• Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability.

  1995cited by this paper
• Steroid hormone receptors: many actors in search of a plot.

  1995cited by this paper
• Resistance to transforming growth factor beta and activin due to reduced receptor expression in human breast tumor cell lines.

  1995cited by this paper
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  1995cited by this paper
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  1995cited by this paper
• The nuclear receptor superfamily: the second decade.

  1995cited by this paper
• Relationship between tamoxifen-induced transforming growth factor beta 1 expression, cytostasis and apoptosis in human breast cancer cells.

  1995cited by this paper
• Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats.

  1994cited by this paper
• Effects of tamoxifen on uterus and ovaries of postmenopausal women in a randomised breast cancer prevention trial.

  1994cited by this paper
• Expression of transforming growth factor beta type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells.

  1994cited by this paper
• Characterization of the proximal estrogen-responsive element of human cathepsin D gene.

  1994cited by this paper
• Expression of transforming growth factor β type II receptor leads to reduced malignancy in human breast cancer MCF-7 cells

  1994cited by this paper
• Phosphorylated CREB binds specifically to the nuclear protein CBP

  1993cited by this paper
• Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer.

  1992cited by this paper
• The strategic use of antiestrogens to control the development and growth of breast cancer.

  1992cited by this paper
• Role of the two activating domains of the oestrogen receptor in the cell‐type and promoter‐context dependent agonistic activity of the anti‐oestrogen 4‐hydroxytamoxifen.

  1990cited by this paper
• Cooperative effects of colony-stimulating factor 1 and recombinant interleukin 2 on proliferation and induction of cytotoxicity of macrophage precursors generated from mouse bone marrow cell cultures

  1989cited by this paper
• The human estrogen receptor has two independent nonacidic transcriptional activation functions.

  1989cited by this paper
• The steroid and thyroid hormone receptor superfamily.

  1988cited by this paper
• Functional domains of the human estrogen receptor.

  1987cited by this paper
• Localisation of the oestradiol‐binding and putative DNA‐binding domains of the human oestrogen receptor.

  1986cited by this paper

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  2022cites this paper
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  2021cites this paper
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  2019cites this paper
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  2019cites this paper
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  2019cites this paper
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  2018cites this paper
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  2018cites this paper
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  2018cites this paper
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  2017cites this paper
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  2016cites this paper
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• Effects of psoralens as anti-tumoral agents in breast cancer cells.

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  2014cites this paper
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• FKBPL regulates estrogen receptor signaling and determines response to endocrine therapy.

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• Recurrent pregnancy loss: A disease of inflammation and coagulation

  2009cites this paper
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  2009cites this paper
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  2009cites this paper
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• Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (review).

  2009cites this paper
• Estrogen-TGFbeta cross-talk in bone and other cell types: role of TIEG, Runx2, and other transcription factors.

  2008cites this paper
• Prognostic Significance of TGF‚-1 and pSmad2/3 in Breast Cancer Patients with T 1-2 ,N 0 Tumours

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• Role of TGF-β in Osteolytic Bone Metastases

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  2008cites this paper
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  2007cites this paper
• Control of prostate cell growth: BMP antagonizes androgen mitogenic activity with incorporation of MAPK signals in Smad1

  2007cites this paper
• Prognostic significance of TGFbeta-1 and pSmad2/3 in breast cancer patients with T1-2,N0 tumours.

  2007cites this paper
• Estrogen receptors alpha and beta are inhibitory modifiers of Apc-dependent tumorigenesis in the proximal colon of Min/+ mice.

  2007cites this paper
• Activin and estrogen crosstalk regulates transcription in human breast cancer cells.

  2007cites this paper
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  2006cites this paper
• Transcription of gonadotropin beta subunit genes involves cross-talk between the transcription factors and co-regulators that mediate actions of the regulatory hormones.

  2006cites this paper
• Role of estrogen receptor alpha transcriptional coregulators in tamoxifen resistance in breast cancer.

  2006cites this paper
• A Dishevelled-1/Smad1 Interaction Couples WNT and Bone Morphogenetic Protein Signaling Pathways in Uncommitted Bone Marrow Stromal Cells*

  2006cites this paper
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  2006cites this paper
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  2006cites this paper
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  2006cites this paper
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  2006cites this paper