Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

Stossi, Fabio; Madak-Erdoğan, Zeynep; Katzenellenbogen, Benita S.

doi:10.1128/mcb.01476-08

Cited by 59 publications

(60 citation statements)

References 42 publications

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“…8A). This effect of CtBP1 ablation is in agreement with previous studies showing that CtBP1 or CtBP2 knockdown attenuated estrogen-stimulated pS2 expression in MCF7 cells (41) and is consistent with the reduced expression of the IGFBP1 gene seen above in CtBP1-deficient cells. Although loss of CtBP1 had no effect on regulation of the GREB1 gene (the gene regulated by estrogen in breast cancer; Fig.…”

Section: Ablation Of Lcor or Ctbp1 Diminishes Expression Of Estrogen supporting

confidence: 81%

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Palijan

Fernandes

Verway

et al. 2009

Journal of Biological Chemistry

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Ligand-dependent corepressor LCoR interacts with the progesterone receptor (PR) and estrogen receptor ER␣ in the presence of hormone. LCoR contains tandem N-terminal PXDLS motifs that recruit C-terminal-binding protein (CtBP) corepressors as well as a C-terminal helix-turn-helix (HTH) domain. Here, we analyzed the function of these domains in coregulation of PR-and ER␣-regulated gene expression. LCoR and CtBP1 colocalize in nuclear bodies that also contain CtBP-interacting protein CtIP and polycomb group repressor complex marker BMI1. Coexpression of CtBP1 in MCF7 or T47D breast cancer cells augmented corepression by LCoR, whereas coexpression of CtIP did not, consistent with direct interaction of LCoR with CtBP1, but not CtIP. The N-terminal region containing the PXDLS motifs is necessary and sufficient for CTBP1 recruitment and essential for full corepression. However, LCoR function was also strongly dependent on the helix-turn-helix domain, as its deletion completely abolished corepression. LCoR, CtBP, and CtIP were recruited to endogenous PR-and ER␣-stimulated genes in a hormone-dependent manner. Similarly, LCoR was recruited to estrogen-repressed genes, whereas hormone treatment reduced CtBP1 binding. Small interfering RNA-mediated knockdown of LCoR or CtBP1 augmented expression of progesterone-and estrogen-stimulated reporter genes as well as endogenous progesterone-stimulated target genes. In contrast, their ablation had gene-specific effects on ER␣-regulated transcription that generally led to reduced gene expression. Taken together, these results show that multiple domains contribute to LCoR function. They also reveal a role for LCoR and CtBP1 as attenuators of progesterone-regulated transcription but suggest that LCoR and CtBP1 can act to enhance transcription of some genes.

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Section: Ablation Of Lcor or Ctbp1 Diminishes Expression Of Estrogen supporting

confidence: 81%

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Palijan

Fernandes

Verway

et al. 2009

Journal of Biological Chemistry

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“…Chromatin immunoprecipitation (ChIP) and ChIP-sequential ChIP (reChIP) assays were performed as described previously (54). The DNA isolated was subjected to quantitative real-time PCR with 36B4 used as an internal control, and a recruitment index was calculated (ratio of the specific antibody signal over the IgG signal).…”

Section: Methodsmentioning

confidence: 99%

“…he nuclear hormone receptor estrogen receptor ␣ (ER␣) is a master regulator of gene expression and the proliferative program of breast cancer cells (18,29,36,38,50,54) and, hence, is the main target of endocrine therapies. Approximately 70% of human breast tumors express ER␣ and depend on estrogens for growth, rendering these tumors amenable to treatment with drugs such as selective estrogen receptor modulators/antiestrogens (such as tamoxifen) and aromatase inhibitors, which are quite effective and have relatively few side effects.…”

mentioning

confidence: 99%

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex

Bhatt

Xiao

Meng

et al. 2012

Molecular and Cellular Biology

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The nuclear hormone receptor estrogen receptor ␣ (ER␣) mediates the actions of estrogens in target cells and is a master regulator of the gene expression and proliferative programs of breast cancer cells. The presence of ER␣ in breast cancer cells is crucial for the effectiveness of endocrine therapies, and its loss is a hallmark of endocrine-insensitive breast tumors. However, the molecular mechanisms underlying the regulation of the cellular levels of ER␣ are not fully understood. Our findings reveal a unique cellular pathway involving the p38 mitogen-activated protein kinase (p38MAPK)-mediated phosphorylation of ER␣ at Ser-294 that specifies its turnover by the SCF Skp2 proteasome complex. Consistently, we observed an inverse relationship between ER␣ and Skp2 or active p38MAPK in breast cancer cell lines and human tumors. ER␣ regulation by Skp2 was cell cycle stage dependent and critical for promoting the mitogenic effects of estradiol via ER␣. Interestingly, by the knockdown of Skp2 or the inhibition of p38MAPK, we restored functional ER␣ protein levels and the control of gene expression and proliferation by estrogen and antiestrogen in ER␣-negative breast cancer cells. Our findings highlight a novel pathway with therapeutic potential for restoring ER␣ and the responsiveness to endocrine therapy in some endocrine-insensitive ER␣-negative breast cancers. T he nuclear hormone receptor estrogen receptor ␣ (ER␣) is a master regulator of gene expression and the proliferative program of breast cancer cells (18,29,36,38,50,54) and, hence, is the main target of endocrine therapies. Approximately 70% of human breast tumors express ER␣ and depend on estrogens for growth, rendering these tumors amenable to treatment with drugs such as selective estrogen receptor modulators/antiestrogens (such as tamoxifen) and aromatase inhibitors, which are quite effective and have relatively few side effects. These ER␣-targeted therapies (7,27,28,40,41) have resulted in a steady decline in the rate of mortality due to breast cancer but show effectiveness only against ER-positive breast tumors, while ER-negative tumors fail to respond. The regulation of the cellular level of ER␣ is therefore key to the effectiveness of endocrine therapies in breast cancer, and an understanding of its underlying mechanism is critical for the identification of novel drug targets for the design of combinatorial therapies.ER␣ is unusual among nuclear hormone receptors in being a rapidly turning-over protein with a half-life of ca. 4 h in breast cancer cells and in normal target tissues such as the uterus (2, 16, 39), indicating dynamic regulation by modulating factors. The degradation of ER␣, and several other nuclear receptors, has been shown to be under the control of the ubiquitin (Ub) proteasome system (2, 31, 32, 48, 51), yet many important aspects of this regulation remain unclear. In view of the importance of ER␣ in many target tissues and in breast cancer biology, prognosis, and responses to endocrine treatments, we have investigated the underlyin...

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“…SRC-3), leading to histone acetylation and engagement of RNA polymerase II (Pol II), the transcriptional activation status would be maintained. Alternatively, ERα can cause transcriptional repression by recruiting, via p300, CtBP1-containing repressor complexes which lead to RNA polymerase II dismissal and histone deacetylation (Fig 4) (Stossi et al, 2009). In addition, the breast cancer susceptibility gene BRCA1 can strongly inhibits the transcriptional activity of ERα in human breast and prostate cancer cell lines, and this event is correlates with its down-regulation of p300 (but not CBP) (Fan et al, 2002).…”

Section: P300/cbpmentioning

confidence: 99%

Histone Modification and Breast Cancer

Luo¹,

Guo²,

Guo³

et al. 2011

Breast Cancer - Focusing Tumor Microenvironment, Stem Cells and Metastasis

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Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

Cited by 59 publications

References 42 publications

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex

Histone Modification and Breast Cancer

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Estrogen Receptor Alpha Represses Transcription of Early Target Genes via p300 and CtBP1

Cited by 59 publications

References 42 publications

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Ligand-dependent Corepressor LCoR Is an Attenuator of Progesterone-regulated Gene Expression

Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCFSkp2Proteasomal Complex

Histone Modification and Breast Cancer

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Phosphorylation by p38 Mitogen-Activated Protein Kinase Promotes Estrogen ReceptorαTurnover and Functional Activity via the SCF^Skp2Proteasomal Complex