COUP-TF II homodimers are formed in preference to heterodimers with RXRα or TRβ in intact cells

Butler, Alison Jane; Parker, Malcolm G.

doi:10.1093/nar/23.20.4143

Cited by 45 publications

(33 citation statements)

References 43 publications

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“…This is in sharp contrast to COUP TF I and SF1, which, under the same conditions and using the appropriate antibodies, are homodimeric (Fig. 1B, lanes 5 and 6) (44,49) and monomeric (Fig. 1B, lanes 7 and 8) (50), respectively, independent of binding to the DR0 probe.…”

Section: Homodimerization and Trif Complex Formation Of Gcnfmentioning

confidence: 76%

Evolutionary Trace-based Peptides Identify a Novel Asymmetric Interaction That Mediates Oligomerization in Nuclear Receptors

Morgan

Sattar

et al. 2005

Journal of Biological Chemistry

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Germ cell nuclear factor (GCNF) is an orphan nuclear receptor that plays important roles in development and reproduction, by repressing the expression of essential genes such as Oct4, GDF9, and BMP15, through binding to DR0 elements. Surprisingly, whereas recombinant GCNF binds to DR0 sequences as a homodimer, endogenous GCNF does not exist as a homodimer but rather as part of a large complex termed the transiently retinoid-induced factor (TRIF). Here, we use evolutionary trace (ET) analysis to design mutations and peptides that probe the molecular basis for the formation of this unusual complex. We find that GCNF homodimerization and TRIF complex formation are DNA-dependent, and ET suggests that dimerization involves key functional sites on both helix 3 and helix 11, which are located on opposing surfaces of the ligand binding domain. Targeted mutations in either helix of GCNF disrupt the formation of both the homodimer and the endogenous TRIF complex. Moreover, peptide mimetics of both of these ET-determined sites inhibit dimerization and TRIF complex formation. This suggests that a novel helix 3-helix 11 heterotypic interaction mediates GCNF interaction and would facilitate oligomerization. Indeed, it was determined that the endogenous TRIF complex is composed of a GCNF oligomer. These findings shed light on an evolutionarily selected mechanism that reveals the unusual DNAbinding, dimerization, and oligomerization properties of GCNF.

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Section: Homodimerization and Trif Complex Formation Of Gcnfmentioning

confidence: 76%

Evolutionary Trace-based Peptides Identify a Novel Asymmetric Interaction That Mediates Oligomerization in Nuclear Receptors

Morgan

Sattar

et al. 2005

Journal of Biological Chemistry

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“…It has been believed that HNF-4 binds to its response elements exclusively as homodimers (Jiang et al 1995, Jiang & Sladek 1997 and that COUP-TFII binds to its response elements preferentially as homodimers (Butler & Parker 1995). In this study, we did not intend to determine whether HNF-4 , HNF-4 and COUP-TFII bind to the GHR 196/ 178 as homodimer or heterodimers, but the result that one of the DNA-protein complexes (C1 in Fig.…”

Section: Discussionmentioning

confidence: 89%

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and hepatocyte nuclear factor 4gamma (HNF-4gamma) and HNF-4alpha regulate the bovine growth hormone receptor 1A promoter through a common DNA element

Walther²,

Jiang

2004

Journal of Molecular Endocrinology

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The growth hormone receptor (GHR) 1A promoter is responsible for transcription of the liver-specific GHR mRNA variant 1A in several mammalian species. We previously found that the region between nucleotide −218 and nucleotide −151 (relative to the major transcription start site) of the bovine GHR 1A promoter contained a binding site between −196 and −178 for the liver-enriched transcription factor hepatocyte nuclear factor 4 (HNF-4 ) and that the same region might also interact with additional transcription factors in the liver. Using the −218/−151 region as bait to screen a bovine liver cDNA library in a yeast one-hybrid analysis, we identified chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and HNF-4 , as well as HNF-4 , as binding proteins to the −218/−151 region. These binding proteins were also identified in a second yeast one-hybrid analysis using the −196/−178 region as bait, suggesting that COUP-TFII, HNF-4 and HNF-4 all bind to the −196/−178 region. Electrophoretic mobility shift assays confirmed the ability of these three transcription factors in bovine liver nuclear extracts to interact with the −196/−178 region. These interactions also appeared to exist in vivo, as the GHR 1A promoter containing the −196/−178 region could be recovered by immunoprecipitation of the bovine liver chromatin with antibody against COUP-TFII, HNF-4 or HNF-4 . In co-transfection analyses, each of these three transcription factors could activate GHR 1A promoter and the activation was dependent on the −196/−178 region. These results together identify COUP-TFII, HNF-4 and HNF-4 as transcription factors regulating GHR 1A promoter activity through binding to a common DNA element.

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“…The luciferase reporter harboring 5 Gal4-binding sites was previously described (45). The complete coding sequence of the human RARα (NM_000964) was amplified by PCR and cloned into the PSG-VP16 vector (46). The N-CoR C-terminal receptor-interacting domain (amino acids 1,946-2,453) was amplified by PCR and cloned into the EcoRI site of the GALdbd(1-147) expression vector, pSG424 (47).…”

Section: Methodsmentioning

confidence: 99%

CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells

Si¹,

Mueller²,

Collins³

2007

J. Clin. Invest.

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Retinoic acid receptors (RARs) are members of the nuclear hormone receptor family and regulate the proliferation and differentiation of multiple different cell types, including promyelocytic leukemia cells. Here we describe a biochemical/functional interaction between the Ca 2+ /calmodulin-dependent protein kinases (CaMKs) and RARs that modulates the differentiation of myeloid leukemia cells. We observe that CaMKIIγ is the CaMK that is predominantly expressed in myeloid cells. CaMKII inhibits RAR transcriptional activity, and this enzyme directly interacts with RAR through a CaMKII LxxLL binding motif. CaMKIIγ phosphorylates RARα both in vitro and in vivo, and this phosphorylation inhibits RARα activity by enhancing its interaction with transcriptional corepressors. In myeloid cell lines, CaMKIIγ localizes to RAR target sites within myeloid gene promoters but dissociates from the promoter upon retinoic acid-induced myeloid cell differentiation. KN62, a pharmacological inhibitor of the CaMKs, enhances the terminal differentiation of myeloid leukemia cell lines, and this is associated with a reduction in activated (autophosphorylated) CaMKII in the terminally differentiating cells. These observations reveal a significant cross-talk between Ca 2+ and retinoic acid signaling pathways that regulates the differentiation of myeloid leukemia cells, and they suggest that CaMKIIγ may provide a new therapeutic target for the treatment of certain human myeloid leukemias. IntroductionHematopoiesis involves an intricate, functional interaction between lineage-specific cytokines and lineage-specific transcription factors. Among these transcription factors the retinoic acid receptors (RARs) are important regulators of myeloid lineage differentiation. These receptors are members of the ligand-activated nuclear receptor family and include 2 distinct families, the RARs and retinoid X receptors (RXRs), which bind as RAR/RXR heterodimers to their specific target sequences, the retinoic acid response elements (RAREs). RARs play a critical role in regulating myeloid differentiation, since retinoic acid (RA) stimulates the granulocytic differentiation of normal hematopoietic precursors (1), and knockout mice deficient in both RARα and RARγ exhibit a block to granulocyte differentiation (2). Moreover, a critical genetic event in the development of human acute promyelocytic leukemia (APL) involves the acquisition of a t(15;17) chromosome translocation resulting in the leukemogenic PML-RARα fusion protein that acts as a dominant-negative RAR to block normal myeloid differentiation (3,4). This differentiation block can be overcome with relatively high, pharmacological concentrations of RA, and the clinical use of RA to induce terminal differentiation of leukemia cells has had a remarkably beneficial impact on the therapy of APL (5, 6).Ligand binding to RAR/RXR alters its transcriptional activity by triggering a conformational change in this complex that inhibits its interaction with transcriptional corepressors while enhancing interaction ...

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COUP-TF II homodimers are formed in preference to heterodimers with RXRα or TRβ in intact cells

Cited by 45 publications

References 43 publications

Evolutionary Trace-based Peptides Identify a Novel Asymmetric Interaction That Mediates Oligomerization in Nuclear Receptors

Evolutionary Trace-based Peptides Identify a Novel Asymmetric Interaction That Mediates Oligomerization in Nuclear Receptors

Chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and hepatocyte nuclear factor 4gamma (HNF-4gamma) and HNF-4alpha regulate the bovine growth hormone receptor 1A promoter through a common DNA element

CaMKII regulates retinoic acid receptor transcriptional activity and the differentiation of myeloid leukemia cells

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