scholarly journals Smad-Dependent Recruitment of a Histone Deacetylase/Sin3A Complex Modulates the Bone Morphogenetic Protein-Dependent Transcriptional Repressor Activity of Nkx3.2

2003 ◽  
Vol 23 (23) ◽  
pp. 8704-8717 ◽  
Author(s):  
Dae-Won Kim ◽  
Andrew B. Lassar
Keyword(s):  
Transcription Factor ◽  
Bone Morphogenetic Protein ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Transcriptional Repressor ◽  
Bmp Signaling ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
Morphogenetic Protein ◽  
Repressor Activity

ABSTRACT We have previously shown that Nkx3.2, a transcriptional repressor that is expressed in the sclerotome and developing cartilage, can activate the chondrocyte differentiation program in somitic mesoderm in a bone morphogenetic protein (BMP)-dependent manner. In this work, we elucidate how BMP signaling modulates the transcriptional repressor activity of Nkx3.2. We have found that Nkx3.2 forms a complex, in vivo, with histone deacetylase 1 (HDAC1) and Smad1 and -4 in a BMP-dependent manner. The homeodomain and NK domain of Nkx3.2 support the interaction of this transcription factor with HDAC1 and Smad1, respectively, and both of these domains are required for the transcriptional repressor activity of Nkx3.2. Furthermore, the recruitment of an HDAC/Sin3A complex to Nkx3.2 requires that Nkx3.2 interact with Smad1 and -4. Indeed, Nkx3.2 both fails to associate with the HDAC/Sin3A complex and represses target gene transcription in a cell line lacking Smad4, but it performs these functions if exogenous Smad4 is added to these cells. While prior work has indicated that BMP-dependent Smads can support transcriptional activation, our findings indicate that BMP-dependent Smads can also potentiate transcriptional repression, depending upon the identity of the Smad-interacting transcription factor.

scholarly journals Temporal Recruitment of the mSin3A-Histone Deacetylase Corepressor Complex to the ETS Domain Transcription Factor Elk-1

2001 ◽  
Vol 21 (8) ◽  
pp. 2802-2814 ◽  
Author(s):  
Shen-Hsi Yang ◽  
Elaine Vickers ◽  
Alexander Brehm ◽  
Tony Kouzarides ◽  
Andrew D. Sharrocks
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Activation ◽  
Hormone Receptors ◽  
Target Genes ◽  
Mitogen Activated Protein Kinase ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
Corepressor Complex ◽  
Eukaryotic Genes

ABSTRACT The transcriptional status of eukaryotic genes is determined by a balance between activation and repression mechanisms. The nuclear hormone receptors represent classical examples of transcription factors that can regulate this balance by recruiting corepressor and coactivator complexes in a ligand-dependent manner. Here, we demonstrate that the equilibrium between activation and repression via a single transcription factor, Elk-1, is altered following activation of the Erk mitogen-activated protein kinase cascade. In addition to its C-terminal transcriptional activation domain, Elk-1 contains an N-terminal transcriptional repression domain that can recruit the mSin3A-histone deacetylase 1 corepressor complex. Recruitment of this corepressor is enhanced in response to activation of the Erk pathway in vivo, and this recruitment correlates kinetically with the shutoff of one of its target promoters, c-fos. Elk-1 therefore undergoes temporal activator-repressor switching and contributes to both the activation and repression of target genes following growth factor stimulation.

scholarly journals Histone Deacetylase 1 Can Repress Transcription by Binding to Sp1

1999 ◽  
Vol 19 (8) ◽  
pp. 5504-5511 ◽  
Author(s):  
Angelika Doetzlhofer ◽  
Hans Rotheneder ◽  
Gerda Lagger ◽  
Manfred Koranda ◽  
Vladislav Kurtev ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Histone Deacetylase ◽  
Transcriptional Repression ◽  
Trichostatin A ◽  
Dependent Manner ◽  
Histone Deacetylase 1 ◽  
3T3 Fibroblasts ◽  
C Terminus ◽  
Histone Deacetylase Inhibitor Trichostatin ◽  
Carboxy Terminal

ABSTRACT The members of the Sp1 transcription factor family can act as both negative and positive regulators of gene expression. Here we show that Sp1 can be a target for histone deacetylase 1 (HDAC1)-mediated transcriptional repression. The histone deacetylase inhibitor trichostatin A activates the chromosomally integrated murine thymidine kinase promoter in an Sp1-dependent manner. Coimmunoprecipitation experiments with Swiss 3T3 fibroblasts and 293 cells demonstrate that Sp1 and HDAC1 can be part of the same complex. The interaction between Sp1 and HDAC1 is direct and requires the carboxy-terminal domain of Sp1. Previously we have shown that the C terminus of Sp1 is necessary for the interaction with the transcription factor E2F1 (J. Karlseder, H. Rotheneder, and E. Wintersberger, Mol. Cell. Biol. 16:1659–1667, 1996). Coexpression of E2F1 interferes with HDAC1 binding to Sp1 and abolishes Sp1-mediated transcriptional repression. Our results indicate that one component of Sp1-dependent gene regulation involves competition between the transcriptional repressor HDAC1 and the transactivating factor E2F1.

scholarly journals B-Cell Translocation Gene 2 (Btg2) Regulates Vertebral Patterning by Modulating Bone Morphogenetic Protein/Smad Signaling

2004 ◽  
Vol 24 (23) ◽  
pp. 10256-10262 ◽  
Author(s):  
Sean Park ◽  
Young Jae Lee ◽  
Ho-Jae Lee ◽  
Tsugio Seki ◽  
Kwon-Ho Hong ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Target Gene ◽  
Bmp Signaling ◽  
Dependent Manner ◽  
Tail Bud ◽  
Adaptor Molecule ◽  
Morphogenetic Protein ◽  
Dose Dependent ◽  
Transcriptional Target

ABSTRACT Btg2 is a primary p53 transcriptional target gene which may function as a coactivator-corepressor and/or an adaptor molecule that modulates the activities of its interacting proteins. We have generated Btg2-null mice to elucidate the in vivo function of Btg2. Btg2-null mice are viable and fertile but exhibit posterior homeotic transformations of the axial vertebrae in a dose-dependent manner. Consistent with its role in vertebral patterning, Btg2 is expressed in the presomitic mesoderm, tail bud, and somites during somitogenesis. We further provide biochemical evidence that Btg2 interacts with bone morphogenetic protein (BMP)-activated Smads and enhances the transcriptional activity of BMP signaling. In view of the genetic evidence that reduced BMP signaling causes posteriorization of the vertebral pattern, we propose that the observed vertebral phenotype in Btg2-null mice is due to attenuated BMP signaling.

scholarly journals An osteogenesis-related transcription factor, core-binding factor A1, is constitutively expressed in the chondrocytic cell line TC6, and its expression is upregulated by bone morphogenetic protein-2

2000 ◽  
Vol 165 (3) ◽  
pp. 579-586 ◽  
Author(s):  
Y Takazawa ◽  
K Tsuji ◽  
A Nifuji ◽  
H Kurosawa ◽  
Y Ito ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Line ◽  
Bone Morphogenetic Protein ◽  
Blot Analysis ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Dependent Manner ◽  
Core Binding Factor ◽  
Morphogenetic Protein ◽  
Binding Factor

Core-binding factor A1 (Cbfa1), also called Pebp2 alpha A/AML3, is a transcription factor that belongs to the runt-domain gene family. Cbfa1-deficient mice are completely incapable of both endochondral and intramembranous bone formation, indicating that Cbfa1 is indispensable for osteogenesis. Maturation of chondrocytes in these mice is also disorganized, suggesting that Cbfa1 may also play a role in chondrogenesis. The aim of this study was to examine the expression and regulation of Pebp2 alpha A/AML3/Cbfa1 expression in the chondrocyte-like cell line, TC6. Northern blot analysis indicated that Cbfa1 mRNA was constitutively expressed as a 6.3 kb message in TC6 cells and the level of Cbfa1 expression was enhanced by treatment with bone morphogenetic protein-2 (BMP2) in a time- and dose-dependent manner. This effect was blocked by an RNA polymerase inhibitor, 5,6-dichloro-1-beta-d-ribofuranosylbenzimidazole, but not by a protein synthesis inhibitor, cycloheximide. Western blot analysis of the cell lysates using polyclonal antibody raised against Cbfa1 indicated that BMP2 treatment increased the Cbfa1 protein level in TC6 cells. In TC6 cells, BMP2 treatment enhanced expression of alkaline phosphatase and type I collagen mRNAs but suppressed that of type II collagen mRNA. In addition to TC6 cells, Cbfa1 mRNA was also expressed in primary cultures of chondrocytes and BMP2 treatment enhanced Cbfa1 mRNA expression in these cells similarly to its effect on TC6 cells. These data indicate that the Pebp2 alpha A/AML3/Cbfa1 gene is expressed in a chondrocyte-like cell line, TC6, and its expression is enhanced by treatment with BMP.

scholarly journals Induction of Ectopic Olfactory Structures and Bone Morphogenetic Protein Inhibition by Rossy, a Group XII Secreted Phospholipase A2

2005 ◽  
Vol 25 (9) ◽  
pp. 3608-3619 ◽  
Author(s):  
Ignacio Muñoz-Sanjuán ◽  
Ali H. Brivanlou
Keyword(s):  
Bone Morphogenetic Protein ◽  
Transcriptional Activation ◽  
Transforming Growth Factor ◽  
Biological Activities ◽  
Transforming Growth Factor Β ◽  
Hydrolytic Activity ◽  
Binding Activity ◽  
Bmp Signaling ◽  
Bioactive Lipids ◽  
Morphogenetic Protein

ABSTRACT The secreted phospholipases A2 (sPLA2s) comprise a family of small secreted proteins with the ability to catalyze the generation of bioactive lipids through glycophospholipid hydrolysis. Recently, a large number of receptor proteins and extracellular binding partners for the sPLA2s have been identified, suggesting that these secreted factors might exert a subset of their broad spectrum of biological activities independently of their enzymatic activity. Here, we describe an activity for the sPLA2 group XII (sPLA2-gXII) gene during Xenopus laevis early development. In the ectoderm, sPLA2-gXII acts as a neural inducer by blocking bone morphogenetic protein (BMP) signaling. Gain of function in embryos leads to ectopic neurogenesis and to the specification of ectopic olfactory sensory structures, including olfactory bulb and sensory epithelia. This activity is conserved in the Drosophila melanogaster, Xenopus, and mammalian orthologs and appears to be independent of the lipid hydrolytic activity. Because of its effect on olfactory neurogenesis, we have renamed this gene Rossy, in homage to the Spanish actress Rossy de Palma. We present evidence that Rossy/sPLA2-gXII can inhibit the transcriptional activation of BMP direct-target gene reporters in Xenopus and mouse P19 embryonic carcinoma cells through the loss of DNA-binding activity of activated Smad1/4 complexes. Collectively, these data represent the first evidence for signaling cross talk between a secreted phospholipase A2 and the BMP/transforming growth factor β pathways and identify Rossy/sPLA2-gXII as the only factor thus far described which is sufficient to induce anterior sensory neural structures during vertebrate development.

scholarly journals The Zinc Finger Transcription Factor Gli2 Mediates Bone Morphogenetic Protein 2 Expression in Osteoblasts in Response to Hedgehog Signaling

2006 ◽  
Vol 26 (16) ◽  
pp. 6197-6208 ◽  
Author(s):  
Ming Zhao ◽  
Mei Qiao ◽  
Stephen E. Harris ◽  
Di Chen ◽  
Babatunde O. Oyajobi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Bone Morphogenetic Protein ◽  
Hedgehog Signaling ◽  
Osteoblast Differentiation ◽  
Promoter Activity ◽  
Bone Morphogenetic Protein 2 ◽  
Dependent Manner ◽  
Genetic Ablation ◽  
Morphogenetic Protein

ABSTRACTBone morphogenetic protein 2 (BMP-2) plays a critical role in osteoblast function. InDrosophila, Cubitus interruptus (Ci), which mediates hedgehog signaling, regulates gene expression ofdpp, the ortholog of mammalian BMP-2. Null mutation of the transcription factor Gli2, a mammalian homolog of Ci, results in severe skeletal abnormalities in mice. We hypothesize that Gli2 regulates BMP-2 gene transcription and thus osteoblast differentiation. In the present study, we show that overexpression of Gli2 enhances BMP-2 promoter activity and mRNA expression in osteoblast precursor cells. In contrast, knocking down Gli2 expression by Gli2 small interfering RNA or genetic ablation of the Gli2 gene results in significant inhibition of BMP-2 gene expression in osteoblasts. Promoter analyses, including chromatin immunoprecipitation and electrophoretic mobility shift assays, provided direct evidence that Gli2 physically interacts with the BMP-2 promoter. Functional studies showed that Gli2 is required for osteoblast maturation in a BMP-2-dependent manner. Finally, Sonic hedgehog (Shh) stimulates BMP-2 promoter activity and osteoblast differentiation, and the effects of Shh are mediated by Gli2. Taken together, these results indicate that Gli2 mediates hedgehog signaling in osteoblasts and is a powerful activator of BMP-2 gene expression, which is required in turn for normal osteoblast differentiation.

scholarly journals Bone morphogenetic protein 2 inhibits growth differentiation factor 8-induced cell signaling via upregulation of gremlin2 expression in human granulosa-lutein cells

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Xiaoyan Luo ◽  
Hsun-Ming Chang ◽  
Yuyin Yi ◽  
Yingpu Sun ◽  
Peter C. K. Leung
Keyword(s):  
Bone Morphogenetic Protein ◽  
Molecular Mechanisms ◽  
Kinase Inhibitors ◽  
Bmp Signaling ◽  
Bone Morphogenetic Protein 2 ◽  
Type I ◽  
Dependent Manner ◽  
Small Interfering Rnas ◽  
Differentiation Factor ◽  
Morphogenetic Protein

Abstract Background Bone morphogenetic protein 2 (BMP2), growth differentiation factor 8 (GDF8) and their functional receptors are expressed in human ovarian follicles, and these two intrafollicular factors play essential roles in regulating follicle development and luteal function. As BMP antagonists, gremlin1 (GREM1) and gremlin2 (GREM2) suppress BMP signaling through blockage of ligand-receptor binding. However, whether BMP2 regulates the expression of GREM1 and GREM2 in follicular development remains to be determined. Methods In the present study, we investigated the effect of BMP2 on the expression of GREM1 and GREM2 and the underlying mechanisms in human granulosa-lutein (hGL) cells. An established immortalized human granulosa cell line (SVOG) and primary hGL cells were used as study models. The expression of GREM1 and GREM2 were examined following cell incubation with BMP2 at different concentrations and time courses. The TGF-β type I inhibitors (dorsomorphin, DMH-1 and SB431542) and small interfering RNAs targeting ALK2, ALK3, SMAD2/3, SMAD1/5/8 and SMAD4 were used to investigate the involvement of the SMAD-dependent pathway. Results Our results showed that BMP2 significantly increased the expression of GREM2 (but not GREM1) in a dose- and time-dependent manner. Using a dual inhibition approach combining kinase inhibitors and siRNA-mediated knockdown, we found that the BMP2-induced upregulation of GREM2 expression was mediated by the ALK2/3-SMAD1/5-SMAD4 signaling pathway. Moreover, we demonstrated that BMP2 pretreatment significantly attenuated the GDF8-induced phosphorylation of SMAD2 and SMAD3, and this suppressive effect was reversed by knocking down GREM2 expression. Conclusions Our findings provide new insight into the molecular mechanisms by which BMP2 modulates the cellular activity induced by GDF8 through the upregulated expression of their antagonist (GREM2).

scholarly journals Activation of the Bone Morphogenetic Protein Signaling Pathway Induces Inhibin βB-Subunit mRNA and Secreted Inhibin B Levels in Cultured Human Granulosa-Luteal Cells

2002 ◽  
Vol 87 (3) ◽  
pp. 1254-1261 ◽  
Author(s):  
Risto Jaatinen ◽  
Jonas Bondestam ◽  
Taneli Raivio ◽  
Kristiina Hildén ◽  
Leo Dunkel ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Granulosa Cell ◽  
Bmp Signaling ◽  
Inhibin B ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Subunit Mrna ◽  
Morphogenetic Protein

During the human menstrual cycle the circulating levels of inhibin B, a dimer of inhibin α- and βB-subunits, fluctuate in a fashion distinct from that of inhibin A, the α-βA-subunit dimer. This suggests that human inhibin subunits are each regulated in a distinct manner in human ovarian granulosa cells by endocrine and local factors. We have previously shown using cultures of human granulosa-luteal (hGL) cells that gonadotropins stimulate the steady state mRNA levels of inhibin α- and βA-subunits, but not those of the βB-subunit, which, on the other hand, are up-regulated by, for instance, activin and TGFβ. We recently identified the TGFβ gene family member bone morphogenetic protein-3 (BMP-3) as a granulosa cell-derived growth factor, but whether BMP-3 or other structurally related BMPs regulate human granulosa cell inhibin production is not known. We show here that hGL cells express mRNAs for distinct serine/threonine kinase receptors (BMP-RIA and BMP-RII) and Smad signaling proteins (Smad1, Smad4, and Smad5) involved in the mediation of cellular effects of BMPs. Subsequently, we determined in hGL cell cultures the effects of distinct members of the BMP family previously found to be expressed in mammalian ovaries. Recombinant BMP-2 induces potently in a time- and concentration-dependent manner the expression of the inhibin βB-subunit mRNAs in hGL cells without affecting the levels of α- or βA-subunit mRNAs. BMP-6 has a similar, but weaker, effect than BMP-2, whereas BMP-3 and its close homolog, BMP-3b (also known as growth differentiation factor-10) had no effect on inhibin subunit mRNA expression. hCG treatment of hGL cells was previously shown to abolish the stimulatory effect of activin on βB-subunit mRNA levels, and here hCG is also shown to suppress the effect of BMP-2. Furthermore, BMP-2 stimulates hGL cell secreted dimeric inhibin B levels in a concentration-dependent manner. Depending on the experiment, maximal increases in inhibin B levels of 6- to 28-fold above basal levels were detected during a 72-h culture period. We conclude that activation of the BMP-signaling pathway in hGL cells stimulates inhibin βB-subunit mRNA levels and leads at the protein level to a dramatic stimulation of secreted inhibin B dimers. Our results are consistent with the suggestion that in addition to the distinct activin- and TGFβ-activated signaling pathways, the BMP-activated pathway is likely to be implicated in the complex regulation of inhibins in the human ovary.

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