Corepressors in Mediating Repression by Nuclear Receptors

Jepsen, Kristen; Rosenfeld, Michael G.

doi:10.1016/b978-012124546-7/50636-7

Cited by 24 publications

(33 citation statements)

References 65 publications

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“…In this sense, some nuclear proteins such as histone H3, estrogen receptor (ER), and the SMRT corepressor are direct substrates for IKK␣ kinase activity (18,20,21,23). Nuclear corepressors are crucial for the formation of repression complexes; therefore, changes in their subcellular distribution should have striking effects on the overall regulation of transcription (39). This is the case for cytoplasmic translocation of N-CoR after Akt-dependent phosphorylation that is required for astrocyte differentiation (40), the aberrant recruitment of SMRT by PML-RAR in myeloid leukemias (41), or down-regulation of SMRT in non-Hodgkin lymphomas (42).…”

Section: Discussionmentioning

confidence: 99%

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Fernández‐Majada

Aguilera

Villanueva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

124

110

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Nuclear functions for IκB kinase (IKK), including phosphorylation of histone H3 and nuclear corepressors, have been recently described. Here, we show that IKK is activated in colorectal tumors concomitant with the presence of phosphorylated SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor that is aberrantly localized in the cytoplasm. In these tumors, IKKα associates to the chromatin of specific Notch targets, leading to the release of SMRT. Abrogation of IKK activity by BAY11-7082 or by expressing dominant negative IKKα restores the association of SMRT with Notch target genes, resulting in specific gene repression. Finally, BAY11-7082 significantly reduces tumor size in colorectal cancer xenografts (CRC-Xs) implanted in nude mice.

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Section: Discussionmentioning

confidence: 99%

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Fernández‐Majada

Aguilera

Villanueva

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

124

110

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“…The repression domains in NCoR and SMRT recruit different HDAC-containing complexes (22). Because the SAFB1RD-mediated repression was partially released by treatment with HDAC inhibitors, we expected that a yeast two-hybrid assay using SAFB1RD as bait would reveal an interaction with known HDACs or members of the HDAC complexes.…”

Section: Discussionmentioning

confidence: 99%

“…Conventional repression assays using Gal4-DBD fusion proteins and a Gal4-responsive reporter construct were performed with CV-1 cells, and the N-terminal repression domain (RD) of SMRT (SMRTRD) (aa 1-1230) was used as a positive control (22). The Gal4-DBD-SMRTRD and -SAFB1 fusion proteins were expressed at comparable levels (Fig.…”

Section: Safb1 Binds Rna But This Function Is Not Required Formentioning

confidence: 99%

“…These independent repression domains recruit proteins that modulate activity by remodeling local chromatin or by interacting directly with members of the basal transcription machinery. For example, SMRT, NCoR (22), and metastasis-associated protein 1 (MTA1) (23,24) recruit histone deacetylases (HDAC) or HDAC-containing protein complexes to target promoters. Additionally, NCoR can also function by locking the central components of the transcription initiation machinery (TFIIB and TATA-binding protein-associated factors) into a nonfunctional complex or confirmation that is not favorable for transcription (25).…”

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confidence: 99%

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Structure-Function Analysis of the Estrogen Receptor α Corepressor Scaffold Attachment Factor-B1

Townson

Kang

Lee

et al. 2004

Journal of Biological Chemistry

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Scaffold attachment factor-B1 (SAFB1) is a nuclear matrix protein that has been proposed to couple chromatin structure, transcription, and RNA processing. We have previously shown that SAFB1 can repress estrogen receptor (ER␣)-mediated transactivation. Here we present a structure-function study showing that transactivation is mediated via an intrinsic and transferable Cterminal repression domain (RD). A similar C-terminal RD was found in the family member SAFB2. Removal of the RD from SAFB1 resulted in a dominant-negative SAFB1 protein that increased ligand-dependent and -independent ER␣ activity. SAFB1RD-mediated repression was partly blocked by histone deacetylase inhibitors; however, no histone deacetylase inhibitors were identified in a yeast two-hybrid screen using the RD as bait. Instead, SAFB1RD was found to interact with TAFII68, a member of the basal transcription machinery. We propose a model in which SAFB1 represses ER␣ activity via indirect association with histone deacetylation and interaction with the basal transcription machinery.SAFB1 1 belongs to a family of nuclear proteins that are localized in the nuclear matrix. The matrix is a proteinaceous structure consisting of a network of ribonucleoproteins and non-histone proteins, such as transcription factors, that serve as a scaffold for the higher organization of chromatin into loop structures (1). A characteristic of SAFB family members is the presence of an N-terminal SAF box (2-4) that binds to DNA regulatory regions termed scaffold/matrix attachment regions (S/MARs). S/MARs are bound to the nuclear matrix, define the loop structure of higher order chromatin (5-8), divide the genome into structural and functional domains, and are implicated in the regulation of gene expression (1).SAFB proteins contain a central RNA recognition motive (RRM), which suggests a role in mRNA processing. Because SAFB1 also has been shown to interact with members of the RNA processing machinery and with RNA polymerase II, it has been suggested that this protein is part of a "transcriptosome" complex, coupling chromatin structure to transcription and RNA processing (9 -12).We have previously reported that SAFB1 plays an important role in breast cancer because its overexpression results in growth inhibition (13). SAFB1 maps to a chromosomal locus that displays unusually high rates of loss of heterozygosity (14), and mutations have been identified in breast tumors (14). We have also shown that SAFB1 can bind to and repress transcriptional activity of the estrogen receptor ␣ (ER␣), thereby functioning as an ER␣ corepressor (15).ER␣ is a steroid receptor that regulates transcription of genes involved in proliferation, apoptosis, migration, and other cellular processes (16). ER␣ corepressors and coactivators are components of large protein complexes that tightly control the activity of ER␣ (17,18). Although the role of coactivators in the activity of ER␣ is well established, the role of ER␣ corepressors is less clear. Based on recent studies, it is believed that ER␣ corepr...

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“…Repression by N-CoR and SMRT results from their association with large histone deacetylase complexes, which lead to histone deacetylation, altered chromatin structure, and decreased gene transcription (reviewed in ref. 2). Although few studies have demonstrated that N-CoR expression is regulated at the level of gene transcription, several examples of posttranslational regulation of N-CoR expression and activity have been described.…”

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confidence: 99%

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

Frasor

Danes

Funk

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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C ellular activity is precisely regulated by a finely tuned balance between coactivator and corepressor proteins that control transcriptional networks during development and in normal and cancerous states (1). The corepressors N-CoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoid and thyroid hormone receptors) play crucial roles in transcriptional repression by multiple classes of transcription factors, including some nuclear hormone receptors. Repression by N-CoR and SMRT results from their association with large histone deacetylase complexes, which lead to histone deacetylation, altered chromatin structure, and decreased gene transcription (reviewed in ref. 2). Although few studies have demonstrated that N-CoR expression is regulated at the level of gene transcription, several examples of posttranslational regulation of N-CoR expression and activity have been described. Recent studies have shown that N-CoR interaction with transcription factors, such as NF-B and estrogen receptor (ER), can be reduced through translocation of N-CoR out of the nucleus and into the cytoplasm (3-5). N-CoR has also been shown to be regulated by ubiquitin-mediated protein degradation through an interaction with the E3 ubiquitin ligase Siah2, a mammalian homolog of Drosophila seven in absentia (Sina), which leads to the ubiquitination and degradation of N-CoR by the 26S proteasome (6).The majority of estrogen's effects on its numerous target tissues are mediated by its two receptors, ER␣ and ER␤, which act primarily as ligand-dependent transcription factors. Upon binding to its ligand, the ER associates with DNA either directly at estrogen response elements or through tethering to other transcription factors, leading to the recruitment of transcriptional coregulators and chromatin-modifying complexes and the regulation of gene expression (7). We and others (8-17) have used microarray gene expression profiling to identify estrogen target genes in breast cancer cells, where estrogen has been shown to stimulate proliferation and suppress apoptosis through the regulation of multiple genes. These studies have demonstrated that, as expected, estrogen up-regulates many cell-cycle regulators, growth factors, and antiapoptotic genes but also down-regulates a number of cell-cycle inhibitors and proapoptotic genes.Estrogen also regulates the mRNA expression of important transcriptional regulators, both transcription factors and transcriptional coactivators and corepressors (12). Evidence supporting the idea that 17␤-estradiol (E2) is capable of regulating the expression of coregulators has grown in the past few years. For example, this hormone has been shown to up-regulate mRNA levels for the corepressors RIP140 (12, 18), SHP (19), and SHARP (20) and also to down-regulate mRNA levels for the coactivators 21). In addition to the regulation of mRNA for some coregulators, the activity of these proteins can be modulated by hormone by changing the protein's state of phosphorylation, as observed for the coactivator SRC3͞AIB1...

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Corepressors in Mediating Repression by Nuclear Receptors

Cited by 24 publications

References 65 publications

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Nuclear IKK activity leads to dysregulated Notch-dependent gene expression in colorectal cancer

Structure-Function Analysis of the Estrogen Receptor α Corepressor Scaffold Attachment Factor-B1

Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes

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