Transducin-like Enhancer of Split Proteins, the Human Homologs of Drosophila Groucho, Interact with Hepatic Nuclear Factor 3β

Wang, Jen-Chywan; Waltner-Law, Mary; Yamada, Kazuya; Osawa, Haruhiko; Stifani, Stefano; Granner, Daryl K.

doi:10.1074/jbc.m910211199

Cited by 53 publications

(60 citation statements)

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“…This PCR fragment was then digested by BamHI and XbaI and subcloned into pSG424 plasmid (39). Construction of GAL4-TLE1 and (GAL4)5E1BLuc reporters (40,41) and assays for ␤-galactosidase and luciferase activity (42) have been described previously. A549 cells were maintained in Dulbecco's modified Eagle's medium supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

The Caenorhabditis elegans Ortholog of TRAP240, CeTRAP240/let-19, Selectively Modulates Gene Expression and Is Essential for Embryogenesis

Wang

Walker

Blackwell

et al. 2004

Journal of Biological Chemistry

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Mediator complexes are large multiprotein assemblies that function in the regulation of eukaryotic gene transcription. In yeast, certain mediator subunits appear to comprise a subcomplex that acts in the regulation of a specific subset of genes. We investigated in a metazoan, Caenorhabditis elegans, the roles and interactions of two of those subunits, CeTRAP240/let-19 and Ce-TRAP230/dpy-22. We found that CeTRAP240/let-19 contains four domains that are conserved in the human TRAP240 protein and that one of those domains displays intrinsic transcriptional repression activity. Using RNA interference, we found that reduced expression of Ce-TRAP240/let-19 displayed a high penetrance of embryonic lethality in F1 progeny; animals that escaped embryonic arrest showed mutant phenotypes such as burst vulva and molting defects. CeTRAP240/let-19 appeared to affect specific genes, as CeTRAP240/let-19(RNAi) led to selectively reduced expression of a subset of reporter genes examined. Genetic experiments supported the view that CeTRAP240/let-19 and CeTRAP230/dpy-22, like their Drosophila and yeast counterparts, can operate on common pathways. Thus, a male tail phenotype caused by the pal-1(e2091) mutation was suppressed not only by CeTRAP230/dpy-22 mutants, as reported previously, but also by reduced expression of CeTRAP240/let-19. Additionally, CeTRAP240/let-19(RNAi) in a CeTRAP230/ dpy-22 mutant background produced a strong synthetic lethal phenotype. Overall, our results establish specific roles of CeTRAP240/let-19 in C. elegans embryonic development and a functional interaction between Ce-TRAP240/let-19 and CeTRAP230/dpy-22. Interestingly, whereas this interaction has been conserved from yeast to mammals, the subcomplex modulates metazoanspecific genetic pathways, likely in addition to those also controlled in yeast.

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Section: Methodsmentioning

confidence: 99%

The Caenorhabditis elegans Ortholog of TRAP240, CeTRAP240/let-19, Selectively Modulates Gene Expression and Is Essential for Embryogenesis

Wang

Walker

Blackwell

et al. 2004

Journal of Biological Chemistry

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“…Members of the other subgroup, e.g., Grg5 in mice and AES in humans, contain the amino-terminal region of gro, including the Q-rich domain, but lack most of the variable region and the entire WD-40 repeat region. Mammalian gro homologues in the first group bind to transcription factors that target gene repression (Aronson et al, 1997;Roose et al, 1998;Eberhard et al, 2000;Tetsuka et al, 2000;Wang et al, 2000;Brantjes et al, 2001), whereas the short form of gro, such as XGrg5 in Xenopus, has been shown to enhance transcriptional activity (Roose et al, 1998;Brantjes et al, 2001). It has been speculated that Grg5 may act as a dominant negative molecule within a transcription complex.…”

Section: Introductionmentioning

confidence: 99%

Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Wang

Plotkina

et al. 2002

Developmental Dynamics

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Gene-targeted disruption of Grg5, a mouse homologue of Drosophila groucho (gro), results in postnatal growth retardation in mice. The growth defect, most striking in approximately half of the Grg5 null mice, occurs during the first 4 -5 weeks of age, but most mice recover retarded growth later. We used the nonlinear mixed-effects model to fit the growth data of wild-type, heterozygous, and Grg5 null mice. On the basis of preliminary evidence suggesting an interaction between Grg5 and the transcription factor Cbfa1/Runx2, critical for skeletal development, we further investigated the skeleton in the mice. A long bone growth plate defect was identified, which included shorter zones of proliferative and hypertrophic chondrocytes and decreased trabecular bone formation. This decreased trabecular bone formation is likely caused by a reduced recruitment of osteoblasts into the growth plate region of Grg5 null mice. Like the growth defect, the growth plate and trabecular bone abnormality improved as the mice grew older. The growth plate defect was associated with reduced Indian hedgehog expression and signaling. We suggest that Grg5, a transcriptional coregulator, modulates the activities of transcription factors, such as Cbfa1/Runx2 in vivo to affect Ihh expression and the function of long bone growth plates.

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“…Interestingly, recent studies have shown that the transducin-like enhancer of split (TLE, a mammalian Groucho homolog) protein directly interacts with region II sequences of the HNF-3␤ activation domain and that HNF-3␤ interactions with TLE protein diminish its transcriptional activation in cotransfection assays. 43 Given the fact that increased hepatic HNF-3␤ levels caused decreases in many of its regulatory partners required for synergistic transcriptional activation of hepatocyte genes, HNF-3␤ interaction with the Groucho ESP1 homolog provides a plausible explanation for the observed repression of HNF-3␤ target gene expression. In transient-transfection assays HNF-3␤ has been found to regulate the promoter activity of Glut-2 gene and synergize with HNF-1␣ to activate Glut-2 promoter expression.…”

Section: Tan Et Al Hepatology January 2002mentioning

confidence: 99%

Adenovirus-mediated increase in HNF-3β or HNF-3α shows differences in levels of liver glycogen and gene expression

et al. 2002

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We previously generated a transgenic mouse line (T-77) in which increased hepatic expression of the hepatocyte nuclear factor-3␤ (HNF-3␤) protein was used to assess its role in hepatocyte-specific gene transcription. The T-77 transgenic mice displayed elevated serum bile acid and bilirubin levels and a complete absence of hepatic glycogen storage. These postnatal liver defects were associated with diminished expression of hepatocyte genes involved in gluconeogenesis and bile acid transport as well as reduced levels of hepatocyte transcription factors. In this study, we show that mouse tail vein injections of adenovirus expressing the rat HNF-3␤ (AdHNF3␤) cDNA efficiently increased its levels throughout the liver lobule and recapitulated the T-77 transgenic liver phenotype within several days postinfection. Likewise, the AdHNF3␤-infected liver phenotype was associated with reduced hepatic expression of genes involved in glucose homeostasis, bile acid transport, and bilirubin conjugation, which were not found with control adenovirus infections. These studies show that adenovirus-mediated gene transfer is an effective method for rapid hepatic increases in transcription factor levels to determine in vivo target genes. In contrast, AdHNF3␣-infected liver displayed only a transient reduction in hepatic glycogen levels and was associated with less severe decreases in hepatic expression of gluconeogenic and bilirubin metabolism genes. Consistent with these findings, only T-77 transgenic and AdHNF3␤-infected liver exhibited diminished hepatic expression of the HNF-6 transcription factor, suggesting that reduced HNF-6 levels contribute to diminished HNF-3␤-specific transcriptional activity. T he liver performs essential functions in the body by transcriptionally regulating expression of hepatocyte-specific genes encoding plasma proteins and enzymes involved in glucose metabolism, gluconeogenesis and glycogen storage, and cholesterol and bile acid homeostasis. 1,2 Functional analysis of numerous hepatocyte-specific regulatory regions reveals that they are composed of multiple cis-acting DNA sequences that bind different families of hepatocyte nuclear factors (HNF) genes. 3,4 Although none of these transcription factors is entirely liver specific, the requirement for combinatorial protein interactions among them to achieve high transcriptional levels plays an important role in maintaining hepatocyte-specific gene expression. Isolation of the cDNA clones encoding these HNF proteins facilitated the identification of their DNA binding and transcriptional activation domains. On the basis of homology within the DNA binding domains, the transcription factors were grouped into related protein families. These include the Pou-Homeodomain HNF-1, the winged helix containing Forkhead Box (Fox) HNF-3, the steroid hormone receptor HNF-4, the basic leucine zipper CCAAT/enhancer binding protein (C/EBP), and the One-Cut Homeodomain HNF-6 families. 3,4 The Fox transcription factors 5 are an extensive protein family that shares homology in th...

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Transducin-like Enhancer of Split Proteins, the Human Homologs of Drosophila Groucho, Interact with Hepatic Nuclear Factor 3β

Cited by 53 publications

References 50 publications

The Caenorhabditis elegans Ortholog of TRAP240, CeTRAP240/let-19, Selectively Modulates Gene Expression and Is Essential for Embryogenesis

The Caenorhabditis elegans Ortholog of TRAP240, CeTRAP240/let-19, Selectively Modulates Gene Expression and Is Essential for Embryogenesis

Growth defect in Grg5 null mice is associated with reduced Ihh signaling in growth plates

Adenovirus-mediated increase in HNF-3β or HNF-3α shows differences in levels of liver glycogen and gene expression

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