Binding of Ligands and Activation of Transcription by Nuclear Receptors

Steinmetz, Anke; Renaud, Jean‐Paul; Moras, Dino

doi:10.1146/annurev.biophys.30.1.329

Cited by 199 publications

(144 citation statements)

References 68 publications

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“…Nr4a1 (also known as nur77 and NGFI-B) belongs to a subfamily of orphan nuclear receptors, whose other members are Nr4a2 [also known as Rnr-1 (ribonucleotide reductase-1), Not, and Nurr1] and Nr4a3 [also known as Nor-1 (neuron-derived orphan receptor-1) and Tec], all of which function as transcription factors (Ryseck et al, 1989;Steinmetz et al, 2001). Several studies have implicated Nr4a1 and Nr4a2 as CREB target genes (Fass et al, 2003;Darragh et al, 2005;von Hertzen and Giese, 2005ab).…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Vecsey¹,

Hawk²,

Lattal³

et al. 2007

Journal of Neuroscience

769

761

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Histone deacetylase (HDAC) inhibitors increase histone acetylation and enhance both memory and synaptic plasticity. The current model for the action of HDAC inhibitors assumes that they alter gene expression globally and thus affect memory processes in a nonspecific manner. Here, we show that the enhancement of hippocampus-dependent memory and hippocampal synaptic plasticity by HDAC inhibitors is mediated by the transcription factor cAMP response element-binding protein (CREB) and the recruitment of the transcriptional coactivator and histone acetyltransferase CREB-binding protein (CBP) via the CREB-binding domain of CBP. Furthermore, we show that the HDAC inhibitor trichostatin A does not globally alter gene expression but instead increases the expression of specific genes during memory consolidation. Our results suggest that HDAC inhibitors enhance memory processes by the activation of key genes regulated by the CREB:CBP transcriptional complex.

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Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Vecsey¹,

Hawk²,

Lattal³

et al. 2007

Journal of Neuroscience

769

761

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“…Hop1/Sti1, by virtue of its ability to bind Hsp70 and Hsp90 in tandem, facilitates the transfer of Hsp70-bound receptors to the open form of Hsp90. The Hsp90 system then induces subtle alterations in the conformation of the bound steroid receptor that enhances its affinity toward its respective ligand [41].…”

Section: Hsp90 Client Proteinsmentioning

confidence: 99%

Hsp90—From signal transduction to cell transformation

Brown

Zhu

Schmidt

et al. 2007

Biochemical and Biophysical Research Communications

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The molecular chaperone, Hsp90, facilitates the maturation and/or activation of over 100 'client proteins' involved in signal transduction and transcriptional regulation. Largely an enigma among the families of heat shock proteins, Hsp90 is central to processes broadly ranging from cell cycle regulation to cellular transformation. Here we review the contemporary body of knowledge regarding the biochemical mechanisms of Hsp90 and update the most current paradigms defining its involvement in both normal and pathological cell physiology. KeywordsHsp90; heat shock protein; molecular chaperone; ATPase; genetic capacitor Hsp90 defines a family of molecular chaperones that are highly conserved from prokaryotes to eukaryotes [1][2][3][4][5]. Nonessential for normal growth in most bacteria, Hsp90 is abundantly expressed in higher eukaryotes where it has been shown to be necessary for viability [6,7]. It functions as a homodimer that associates with co-chaperones to catalyze the maturation and/ or activation of over 100 substrate proteins that are known to be involved in cell regulatory pathways [5]. These 'client proteins' include protein kinases, nuclear hormone receptors, transcription factors, and an array of other essential proteins [8]. While much is known regarding the ATPase-driven conformational cycling of Hsp90, the precise physical effects imparted by this chaperone that serve to activate its substrates are still poorly understood [5]. Hsp90 architectureThree highly conserved domains comprise the structure of Hsp90. These include the N-terminal domain, responsible for ATP-binding, a proteolytically resistant core domain, and the Cterminal domain that facilitates homodimerization (Fig. 1a) [9]. In eukaryotes, a more variable charged region links the N-terminal domain to the core domain. The length and composition of this linker region is highly divergent among organisms [10]. As no atomic resolution structure for full-length Hsp90 is yet available, the most thorough structural analyses for Hsp90, to date, have been based on crystallographic studies of its individual domains.A mechanistic understanding of Hsp90 was nebulous until partial sequence homology was recognized between its N-terminal domain and two types of ATP-dependent proteins. These

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“…NRs work in concert with co-activators and co-repressors to regulate gene expression [1]. NRs share a modular domain structure, which includes, from N-terminus to C-terminus, a modulatory A/ B domain, the DNA-binding domain (DBD; C domain), the hinge D domain, the ligand-binding domain (LBD; E domain) and a variable C-terminal F domain [1]. LXRs, like other members of the NR1 family, function as permissive heterodimers with the retinoid X receptors (NR2B1, 2B2, and 2B3).…”

Section: Introductionmentioning

confidence: 99%

Ligand specificity and evolution of liver X receptors

Reschly

Ni²,

Welsh³

et al. 2008

The Journal of Steroid Biochemistry and Molecular Biology

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Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity.

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Binding of Ligands and Activation of Transcription by Nuclear Receptors

Cited by 199 publications

References 68 publications

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Histone Deacetylase Inhibitors Enhance Memory and Synaptic Plasticity via CREB: CBP-Dependent Transcriptional Activation

Hsp90—From signal transduction to cell transformation

Ligand specificity and evolution of liver X receptors

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