scholarly journals Estrogen Receptor β Isoform-Specific Induction of Transforming Growth Factor β-Inducible Early Gene-1 in Human Osteoblast Cells: An Essential Role for the Activation Function 1 Domain

2008 ◽  
Vol 22 (7) ◽  
pp. 1579-1595 ◽  
Author(s):  
John R. Hawse ◽  
Malayannan Subramaniam ◽  
David G. Monroe ◽  
Amanda H. Hemmingsen ◽  
James N. Ingle ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Regulatory Region ◽  
Transforming Growth Factor Β ◽  
Activation Function ◽  
Regulatory Elements ◽  
Early Gene ◽  
Chimeric Receptors ◽  
Steroid Receptor Coactivator ◽  
Estrogen Induction

Abstract The estrogen receptors (ER) α and β are important ligand-mediated transcription factors known to play significant biological roles in numerous tissues including bone. Despite the high homology shared by these receptors, recent studies have suggested that their function is largely unique. Although these receptors have been studied in detail for more than a decade, little data exist concerning the mechanisms by which these two proteins regulate distinct sets of genes. Using the TGFβ-inducible early gene-1 (TIEG) as a model, we demonstrate that TIEG is rapidly induced in response to estrogen in osteoblasts by ERβ, but not ERα. We have identified the regulatory elements utilized by ERβ and have demonstrated that ERβ recruits steroid receptor coactivator (SRC)1 and SRC2 to this regulatory region. Additionally, deletion of the ERβ-activation function 1 (AF1) domain drastically decreases the estrogen induction of TIEG. Through the use of chimeric receptors, we have demonstrated that the AF1 domain of ERβ is responsible for recruiting SRC1 and SRC2 and inducing the expression of TIEG in osteoblasts. Finally, SRC1, but not SRC2, is essential for TIEG induction by ERβ. Overall, these data demonstrate that the estrogen induction of TIEG is ERβ specific and that the AF1 domain of ERβ confers this specificity. Finally, a novel and important role for ERβ’s AF1 is implicated in the recruitment of specific coactivators, suggesting that the AF1 may play a significant role in conferring the differences in regulation of gene expression by these two receptors.

scholarly journals Transforming Growth Factor β Enhances the Glucocorticoid Response of the Mouse Mammary Tumor Virus Promoter through Smad and GA-Binding Proteins

2004 ◽  
Vol 78 (5) ◽  
pp. 2201-2211 ◽  
Author(s):  
Koldo Aurrekoetxea-Hernández ◽  
Elena Buetti
Keyword(s):  
Growth Factor ◽  
Mammary Tumor ◽  
Mouse Mammary Tumor Virus ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Mammary Tumor Virus ◽  
Mouse Mammary Tumor ◽  
Tumor Virus

ABSTRACT Tissue-specific transcription is advantageously investigated by using viral promoters, which are selected for compact regulatory elements. Mouse mammary tumor virus (MMTV) has adapted to specialized cell types and targets initially B lymphocytes. We previously showed that, in B-cell lines, glucocorticoid-induced MMTV transcription requires an ETS family factor, GA-binding protein (GABP), bound in tandem to the MMTV DNA next to the glucocorticoid receptor (GR). We now report that transforming growth factor β (TGF-β) superinduces this response up to 10-fold through binding of its effectors, Smads, between the GABP-binding motifs. The basal level was unaffected. The TGF-β-glucocorticoid cooperation also depended on GR and GABP binding, was transferable to another promoter, and occurred both with transiently transfected and with integrated templates. Smad3 associated in vitro with GR, with GABPα (via the MH2 domain), and with GABPβ, Smad4 only with GABPα. Interactions of Smad3 with GABP (when coexpressed or endogenous to B cells) were shown by coprecipitation and by mammalian two-hybrid assay. This composite DNA element integrates three signaling pathways deriving from TGF-β, glucocorticoid hormones, and a unique ETS factor, and may allow MMTV to exploit factors from the milk. It may as well indicate novel possibilities for cellular regulatory networks.

scholarly journals Transforming growth factor β suppresses peroxisome proliferator-activated receptor γ expression via both SMAD binding and novel TGF-β inhibitory elements

2017 ◽  
Vol 474 (9) ◽  
pp. 1531-1546 ◽  
Author(s):  
Sowmya P. Lakshmi ◽  
Aravind T. Reddy ◽  
Raju C. Reddy
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Context Sensitive ◽  
Signaling Mechanisms ◽  
Target Promoter

Transforming growth factor β (TGF-β) contributes to wound healing and, when dysregulated, to pathological fibrosis. TGF-β and the anti-fibrotic nuclear hormone receptor peroxisome proliferator-activated receptor γ (PPARγ) repress each other's expression, and such PPARγ down-regulation is prominent in fibrosis and mediated, via previously unknown SMAD-signaling mechanisms. Here, we show that TGF-β induces the association of SMAD3 with both SMAD4, needed for translocation of the complex into the nucleus, and the essential context-sensitive co-repressors E2F4 and p107. The complex mediates TGF-β-induced repression by binding to regulatory elements in the target promoter. In the PPARG promoter, we found that the SMAD3–SMAD4 complex binds both to a previously unknown consensus TGF-β inhibitory element (TIE) and also to canonical SMAD-binding elements (SBEs). Furthermore, the TIE and SBEs independently mediated the partial repression of PPARG transcription, the first demonstration of a TIE and SBEs functioning within the same promoter. Also, TGF-β-treated fibroblasts contained SMAD complexes that activated a SMAD target gene in addition to those repressing PPARG transcription, the first finding of such dual activity within the same cell. These findings describe in detail novel mechanisms by which TGF-β represses PPARG transcription, thereby facilitating its own pro-fibrotic activity.

scholarly journals Transforming Growth Factor β-Induced Proliferative Arrest Mediated by TRIM26-Dependent TAF7 Degradation and Its Antagonism by MYC

2017 ◽  
Vol 38 (5) ◽  
Author(s):  
Tadashi Nakagawa ◽  
Masaki Hosogane ◽  
Makiko Nakagawa ◽  
Akane Morohoshi ◽  
Ryo Funayama ◽  
...  
Keyword(s):  
Growth Factor ◽  
Rna Polymerase Ii ◽  
Transforming Growth Factor ◽  
Mammary Epithelial Cells ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β ◽  
Mammary Epithelial ◽  
Regulation Of Transcription ◽  
Gene Promoters ◽  
General Transcription Factor

ABSTRACT Recognition of gene promoters by RNA polymerase II is mediated by general transcription factor IID (TFIID), which has been thought to be a static complex and to play a passive role in the regulation of gene expression under the instruction of gene-specific transcription factors. Here we show that transforming growth factor β (TGF-β) induced degradation of the TFIID subunit TAF7 in cultured mouse mammary epithelial cells and that this effect was required for proliferative arrest in response to TGF-β stimulation. TGF-β stimulated transcription of the gene for the ubiquitin ligase TRIM26, which was shown to ubiquitylate TAF7 and thereby to target it for proteasomal degradation. Sustained exposure of cells to TGF-β resulted in recovery from proliferative arrest in association with amplification of the Myc proto-oncogene, with MYC inhibiting TRIM26 induction by TGF-β. Our data thus show that TFIID is not simply a general mediator of transcription but contributes to the regulation of transcription in response to cell stimulation, playing a key role in the cytostatic function of TGF-β.

scholarly journals Chromatin-Bound p53 Anchors Activated Smads and the mSin3A Corepressor To Confer Transforming Growth Factor β-Mediated Transcription Repression

2008 ◽  
Vol 28 (6) ◽  
pp. 1988-1998 ◽  
Author(s):  
Deepti Srinivas Wilkinson ◽  
Wen-Wei Tsai ◽  
Maria A. Schumacher ◽  
Michelle Craig Barton
Keyword(s):  
Growth Factor ◽  
Tumor Marker ◽  
Transforming Growth Factor ◽  
Hepatoma Cell ◽  
Transforming Growth Factor Β ◽  
Regulatory Elements ◽  
Transcription Repression ◽  
Protein Levels ◽  
Smad Proteins ◽  
Distal Promoter

ABSTRACT In hepatic cells, Smad and SnoN proteins converge with p53 to repress transcription of AFP, an oncodevelopmental tumor marker aberrantly reactivated in hepatoma cells. Using p53- and SnoN-depleted hepatoma cell clones, we define a mechanism for repression mediated by this novel transcriptional partnership. We find that p53 anchors activated Smads and the corepressor mSin3A to the AFP distal promoter. Sequential chromatin immunoprecipitation analyses and molecular modeling indicate that p53 and Smad proteins simultaneously occupy overlapping p53 and Smad regulatory elements to establish repression of AFP transcription. In addition to its well-known function in antagonizing transforming growth factor β (TGF-β) responses, we find that SnoN actively participates in AFP repression by positively regulating mSin3A protein levels. We propose that activation of TGF-β signaling restores a dynamic interplay between p53 and TGF-β effectors that cooperate to effectively target mSin3A to tumor marker AFP and reestablish transcription repression.

scholarly journals Transforming growth factor-β signaling in hypertensive remodeling of porcine aorta

2009 ◽  
Vol 297 (6) ◽  
pp. H2044-H2053 ◽  
Author(s):  
Natasa Popovic ◽  
Eric A. Bridenbaugh ◽  
Jessemy D. Neiger ◽  
Jin-Jia Hu ◽  
Marina Vannucci ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Bone Morphogenetic Proteins ◽  
Vascular Remodeling ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β ◽  
Altered Expression ◽  
Protein Levels ◽  
Extracellular Region

A porcine aortic coarctation model was used to examine regulation of gene expression in early hypertensive vascular remodeling. Aortic segments were collected proximal (high pressure) and distal (low pressure) to the coarctation after 2 wk of sustained hypertension (mean arterial pressure > 150 mmHg). Porcine 10K oligoarrays used for gene expression profiling of the two regions of aorta revealed downregulation of cytoskeletal and upregulation of extracellular region genes relative to the whole genome. A genomic database search for transforming growth factor-β (TGF-β) control elements showed that 19% of the genes that changed expression due to hypertension contained putative TGF-β control elements. Real-time RT-PCR and microarray analysis showed no change in expression of TGF-β1, TGF-β2, TGF-β3, or bone morphogenetic proteins-2 and -4, yet immunohistochemical staining for phosphorylated SMAD2, an indicator of TGF-β signaling, and for phosphorylated SMAD1/5/8, an indicator of signaling through the bone morphogenetic proteins, showed the highest percentage of positively stained cells in the proximal aortic segments of occluded animals. For TGF-β signaling, this increase was significantly different than for sham-operated controls. Western blot analysis showed no difference in total TGF-β1 protein levels with respect to treatment or aortic segment. Immunohistochemistry showed that the protein levels of latency-associated peptide was decreased in proximal segments of occluded animals. Collectively, these results suggest that activation of TGF-β, but not altered expression, may be a major mechanism regulating early hypertensive vascular remodeling.

scholarly journals Epigenetics in Ascending Thoracic Aortic Aneurysm and Dissection

Aorta ◽  
2018 ◽  
Vol 06 (01) ◽  
pp. 001-012 ◽  
Author(s):  
Adeline Boileau ◽  
Mark Lindsay ◽  
Jean-Baptiste Michel ◽  
Yvan Devaux
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Aortic Aneurysm ◽  
Thoracic Aortic Aneurysm ◽  
Transforming Growth Factor ◽  
Regulation Of Gene Expression ◽  
Transforming Growth Factor Β ◽  
Cell Protein ◽  
Monogenic Diseases

AbstractThoracic aortic aneurysm (TAA) is an asymptomatic and progressive dilatation of the thoracic aorta. Ascending aortic dissection (AAD) is an acute intraparietal tear, occurring or not on a pre-existing dilatation. AAD is a condition associated with a poor prognosis and a high mortality rate. TAA and AAD share common etiology as monogenic diseases linked to transforming growth factor β signaling pathway, extracellular matrix defect, or smooth muscle cell protein mutations. They feature a complex pathogenesis including loss of smooth muscle cells, altered phenotype, and extracellular matrix degradation in aortic media layer. A better knowledge of the mechanisms responsible for TAA progression and AAD occurrence is needed to improve healthcare, nowadays mainly consisting of aortic open surgery or endovascular replacement. Recent breakthrough discoveries allowed a deeper characterization of the mechanisms of gene regulation. Since alteration in gene expression has been linked to TAA and AAD, it is conceivable that a better knowledge of the causes of this alteration may lead to novel theranostic approaches. In this review article, the authors will focus on epigenetic regulation of gene expression, including the role of histone methylation and acetylation, deoxyribonucleic acid methylation, and noncoding ribonucleic acids in the pathogenesis of TAA and AAD. They will provide a translational perspective, presenting recent data that motivate the evaluation of the potential of epigenetics to diagnose TAA and prevent AAD.

Novel alleles of the transforming growth factor β-1 regulatory region and exon 1

2015 ◽  
Vol 85 (6) ◽  
pp. 484-491
Author(s):  
E. Arrieta-Bolaños ◽  
J. A. Madrigal ◽  
B. E. Shaw
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Regulatory Region ◽  
Transforming Growth Factor Β ◽  
Exon 1 ◽  
Novel Alleles

scholarly journals NFI-Ski Interactions Mediate Transforming Growth Factor β Modulation of Human Papillomavirus Type 16 Early Gene Expression

2004 ◽  
Vol 78 (8) ◽  
pp. 3953-3964 ◽  
Author(s):  
Amy Baldwin ◽  
Lucia Pirisi ◽  
Kim E. Creek
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Growth Factor ◽  
Binding Sites ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Early Gene ◽  
Early Gene Expression ◽  
Nuclear Extracts ◽  
E6 And E7

ABSTRACT Human papillomaviruses (HPVs) are present in virtually all cervical cancers. An important step in the development of malignant disease, including cervical cancer, involves a loss of sensitivity to transforming growth factor β (TGF-β). HPV type 16 (HPV16) early gene expression, including that of the E6 and E7 oncoprotein genes, is under the control of the upstream regulatory region (URR), and E6 and E7 expression in HPV16-immortalized human epithelial cells is inhibited at the transcriptional level by TGF-β. While the URR contains a myriad of transcription factor binding sites, including seven binding sites for nuclear factor I (NFI), the specific sequences within the URR or the transcription factors responsible for TGF-β modulation of the URR remain unknown. To identify potential transcription factors and binding sites involved in TGF-β modulation of the URR, we performed DNase I footprint analysis on the HPV16 URR using nuclear extracts from TGF-β-sensitive HPV16-immortalized human keratinocytes (HKc/HPV16) treated with and without TGF-β. Differentially protected regions were found to be located around NFI binding sites. Electrophoretic mobility shift assays, using the NFI binding sites as probes, showed decreased binding upon TGF-β treatment. This decrease in binding was not due to reduced NFI protein or NFI mRNA levels. Mutational analysis of individual and multiple NFI binding sites in the URR defined their role in TGF-β sensitivity of the promoter. Overexpression of the NFI family members in HKc/HPV16 decreased the ability of TGF-β to inhibit the URR. Since the oncoprotein Ski has been shown to interact with and increase the transcriptional activity of NFI and since cellular Ski levels are decreased by TGF-β treatment, we explored the possibility that Ski may provide a link between TGF-β signaling and NFI activity. Anti-NFI antibodies coimmunoprecipitated endogenous Ski in nuclear extracts from HKc/HPV16, confirming that NFI and Ski interact in these cells. Ski levels dramatically decreased upon TGF-β treatment of HKc/HPV16, and overexpression of Ski eliminated the ability of TGF-β to inhibit the URR. Based on these studies, we propose that TGF-β inhibition of HPV16 early gene expression is mediated by a decrease in Ski levels, which in turn dramatically reduces NFI activity.

Sign in / Sign up

Export Citation Format

Share Document