Ligand-Dependent Nuclear Receptor Corepressor LCoR Functions by Histone Deacetylase-Dependent and -Independent Mechanisms

Fernandes, Isabelle; Bastien, Yolande; Wai, Timothy; Nygard, Karen; Lin, Roberto; Cormier, Olivier; Lee, Han S.; Eng, Frankie; Bertos, Nicholas; Pelletier, Nicolas; Mader, Sylvie; Han, V. K. M.; Yang, Xiang‐Jiao; White, John H.

doi:10.1016/s1097-2765(03)00014-5

Cited by 229 publications

(213 citation statements)

References 61 publications

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“…Furthermore, emerging evidence indicates that several distinct mechanisms exist to attenuate the ligand-dependent response. For example, ligand-dependent corepressors may recruit histone deacetylases (HDACs) to antagonize the actions of histone acetyltransferases (HATs) and thus reduce chromatin accessibility to the transcriptional machinery (Mazumdar et al 2000;Zheng et al 2001;Fernandes et al 2003). In addition, upon hormone withdrawal, the transcriptional regulatory complexes may be dissembled through the actions of molecular chaperones (Freeman and Yamamoto 2002).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

et al. 2004

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Estrogen receptor ␣ (ER␣) signaling is paramount for normal mammary gland development and function and the repression of breast cancer. ER␣ function in gene regulation is mediated by a number of coactivators and corepressors, most of which are known to modify chromatin structure and/or influence the assembly of the regulatory complexes at the level of transcription initiation. Here we describe a novel mechanism of attenuating the ER␣ activity. We show that cofactor of BRCA1 (COBRA1), an integral subunit of the human negative elongation factor (NELF), directly binds to ER␣ and represses ER␣-mediated transcription. Reduction of the endogenous NELF proteins in breast cancer cells using small interfering RNA results in elevated ER␣-mediated transcription and enhanced cell proliferation. Chromatin immunoprecipitation reveals that recruitment of COBRA1 and the other NELF subunits to endogenous ER␣-responsive promoters is greatly stimulated upon estrogen treatment. Interestingly, COBRA1 does not affect the estrogen-dependent assembly of transcription regulatory complexes at the ER␣-regulated promoters. Rather, it causes RNA polymerase II (RNAPII) to pause at the promoter-proximal region, which is consistent with its in vitro biochemical activity. Therefore, our in vivo work defines the first corepressor of nuclear receptors that modulates ER␣-dependent gene expression by stalling RNAPII. We suggest that this new level of regulation may be important to control the duration and magnitude of a rapid and reversible hormonal response.[Keywords: Nuclear receptor; transcriptional repression; COBRA1; NELF; RNAPII; estrogen] Supplemental material is available at http://www.genesdev.org.

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Section: Discussionmentioning

confidence: 99%

Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

et al. 2004

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“…HDAC6 was also found to be associated with transcriptional corepressors such as LCoR, which is involved in a ligand-dependent repressor activity of nuclear receptors (Fernandes et al, 2003) as well as in that of ETO-2, a component of N-CoR, SMRT and mSin3A complexes (Amann et al, 2001). The repressor activity of individual transcription factors has also been attributed to their association with HDAC6.…”

Section: Nuclear Targets Of Hdac6mentioning

confidence: 95%

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

et al. 2007

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Histone deacetylase 6 (HDAC6) is a unique enzyme with specific structural and functional features. It is actively or stably maintained in the cytoplasm and is the only member, within the histone deacetylase family, that harbors a full duplication of its deacetylase homology region followed by a specific ubiquitin-binding domain at the C-terminus end. Accordingly, this deacetylase functions at the heart of a cellular regulatory mechanism capable of coordinating various cellular functions largely relying on the microtubule network. Moreover, HDAC6 action as a regulator of the HSP90 chaperone activity adds to the multifunctionality of the protein, and allows us to propose a critical role for HDAC6 in mediating and coordinating various cellular events in response to different stressful stimuli.

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“…Many factors equally affect the maximal levels of PR-and GR-mediated gene expression, or V max (McKenna et al, 1999;Giannoukos et al, 2001;Hosohata et al, 2003;Webster et al, 2003;Kino et al, 2004;Zhang et al, 2004;Dong et al, 2005). However, factors that preferentially alter the transactivation of PR vs. GR are being increasingly described (Tan et al, 2000;Fernandes et al, 2003;Metzger et al, 2003;Dhananjayan et al, 2006;Georgiakaki et al, 2006;Sanchez et al, 2007;Zhao et al, 2007). PR is reported to selectively recruit the coactivator SRC-1 and the comodulator CBP to acetylate K5 on histone H4 while GR preferentially recruits TIF2 and then PCAF to histone H3 to cause phosphorylation (S10) and acetylation (K14) and demethylation (K9) .…”

Section: Introductionmentioning

confidence: 99%

Differential modulation of glucocorticoid and progesterone receptor transactivation

Szapary

Song

et al. 2008

Molecular and Cellular Endocrinology

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The determinants of the different biological activities of progesterone receptors (PRs) vs. glucocorticoid receptors (GRs), which bind to the same DNA sequences, remain poorly understood. The mechanisms by which differential expression of a common target gene can be achieved by PR and GR include unequal agonist steroid concentrations for half maximal induction (EC 50 ) and dissimilar amounts of residual partial agonist activity for antisteroids in addition to the more common changes in total gene induction, or V max . Several factors are known to alter some or all of these three parameters for GR-regulated gene induction and some (i.e., the corepressors NCoR and SMRT) modulate the EC 50 and partial agonist activity for GR and PR induction of the same gene in opposite directions. The current study demonstrates that other factors (GME, GMEB-2, Ubc9, and STAMP) can also differentially interact with PRs and GRs or alter several of the above induction parameters under otherwise identical conditions. These results support the hypothesis that the modulation of EC 50 , partial agonist activity, and V max by a given factor is not limited to one receptor in a specific cell line. Furthermore, the number of factors that unequally modulate PR and GR induction parameters is now greatly expanded, thereby increasing the possible mechanisms for differential gene regulation by PRs vs. GRs.

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Ligand-Dependent Nuclear Receptor Corepressor LCoR Functions by Histone Deacetylase-Dependent and -Independent Mechanisms

Cited by 229 publications

References 61 publications

Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

Attenuation of estrogen receptor α-mediated transcription through estrogen-stimulated recruitment of a negative elongation factor

HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination

Differential modulation of glucocorticoid and progesterone receptor transactivation

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