Regulation and function of homeodomain proteins in the embryonic and adult vascular systemsThis paper is one of a selection of papers published in this Special Issue, entitled Young Investigators' Forum.

2007 ◽  
Vol 85 (1) ◽  
pp. 55-65 ◽  
Author(s):  
Josette M. Douville ◽  
Jeffrey T. Wigle
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Vascular System ◽  
Homeobox Genes ◽  
Tube Formation ◽  
Binding Motif ◽  
Homeodomain Proteins ◽  
Downstream Target ◽  
Endothelial Tube Formation ◽  
And Function

During embryonic development, the cardiovascular system first forms and then gives rise to the lymphatic vascular system. Homeobox genes are essential for both the development of the blood and lymphatic vascular systems, as well as for their maintenance in the adult. These genes all encode proteins that are transcription factors that contain a well conserved DNA binding motif, the homeodomain. It is through the homeodomain that these transcription factors bind to the promoters of target genes and regulate their expression. Although many homeodomain proteins have been found to be expressed within the vascular systems, little is known about their downstream target genes. This review highlights recent advances made in the identification of novel genes downstream of the homeodomain proteins that are necessary for regulating vascular cellular processes such as proliferation, migration, and endothelial tube formation. Factors known to regulate the functions of vascular cells via modulating the expression of homeobox genes will be discussed. We will also review current methods used to identify and characterize downstream target genes of homeodomain proteins.

scholarly journals Characterization and target genes of nine human PRD-like homeobox domain genes expressed exclusively in early embryos

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Elo Madissoon ◽  
Eeva-Mari Jouhilahti ◽  
Liselotte Vesterlund ◽  
Virpi Töhönen ◽  
Kaarel Krjutškov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Target Genes ◽  
Genomic Sequence ◽  
Embryonic Stem ◽  
Homeobox Genes ◽  
Preimplantation Embryos ◽  
Human Embryos ◽  
Preimplantation Embryo Development ◽  
Genome Activation

Abstract PAIRED (PRD)-like homeobox genes belong to a class of predicted transcription factor genes. Several of these PRD-like homeobox genes have been predicted in silico from genomic sequence but until recently had no evidence of transcript expression. We found recently that nine PRD-like homeobox genes, ARGFX, CPHX1, CPHX2, DPRX, DUXA, DUXB, NOBOX, TPRX1 and TPRX2, were expressed in human preimplantation embryos. In the current study we characterized these PRD-like homeobox genes in depth and studied their functions as transcription factors. We cloned multiple transcript variants from human embryos and showed that the expression of these genes is specific to embryos and pluripotent stem cells. Overexpression of the genes in human embryonic stem cells confirmed their roles as transcription factors as either activators (CPHX1, CPHX2, ARGFX) or repressors (DPRX, DUXA, TPRX2) with distinct targets that could be explained by the amino acid sequence in homeodomain. Some PRD-like homeodomain transcription factors had high concordance of target genes and showed enrichment for both developmentally important gene sets and a 36 bp DNA recognition motif implicated in Embryo Genome Activation (EGA). Our data implicate a role for these previously uncharacterized PRD-like homeodomain proteins in the regulation of human embryo genome activation and preimplantation embryo development.

scholarly journals Cell transformation mediated by homodimeric E2A-HLF transcription factors.

1997 ◽  
Vol 17 (3) ◽  
pp. 1417-1424 ◽  
Author(s):  
T Inukai ◽  
T Inaba ◽  
T Yoshihara ◽  
A T Look
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Fusion Gene ◽  
Dominant Negative ◽  
Fusion Product ◽  
3T3 Cells ◽  
Par Proteins ◽  
Downstream Target ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

The E2A-HLF fusion gene, created by the t(17;19)(q22;p13) chromosomal translocation in pro-B lymphocytes, encodes an oncogenic protein in which the E2A trans-activation domain is linked to the DNA-binding and protein dimerization domain of hepatic leukemia factor (HLF), a member of the proline- and acidic amino acid-rich (PAR) subfamily of bZIP transcription factors. This fusion product binds to its DNA recognition site not only as a homodimer but also as a heterodimer with HLF and two other members of the PAR bZIP subfamily, thyrotroph embryonic factor (TEF) and albumin promoter D-box binding protein (DBP). Thus, E2A-HLF could transform cells by direct regulation of downstream target genes, acting through homodimeric or heterodimeric complexes, or by sequestering normal PAR proteins into nonfunctional heterocomplexes (dominant-negative interference). To distinguish among these models, we constructed mutant E2A-HLF proteins in which the leucine zipper domain of HLF was extended by one helical turn or altered in critical charged amino acids, enabling the chimera to bind to DNA as a homodimer but not as a heterodimer with HLF or other PAR proteins. When introduced into NIH 3T3 cells in a zinc-inducible vector, each of these mutants induced anchorage-independent growth as efficiently as unaltered E2A-HLF, indicating that the chimeric oncoprotein can transform cells in its homodimeric form. Transformation also depended on an intact E2A activator region, providing further support for a gain-of-function contribution to oncogenesis rather than one based on a dominant-interfering or dominant-negative mechanism. Thus, the tumorigenic effects of E2A-HLF and its mutant forms in NIH 3T3 cells favor a straightforward model in which E2A-HLF homodimers bind directly to promoter/enhancer elements of downstream target genes and alter their patterns of expression in early B-cell progenitors.

scholarly journals Potential Downstream Target Genes of Aberrant ETS Transcription Factors Are Differentially Affected in Ewing’s Sarcoma and Prostate Carcinoma

PLoS ONE ◽  
2012 ◽  
Vol 7 (11) ◽  
pp. e49819 ◽  
Author(s):  
Maria J. Camões ◽  
Paula Paulo ◽  
Franclim R. Ribeiro ◽  
João D. Barros-Silva ◽  
Mafalda Almeida ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Prostate Carcinoma ◽  
Target Genes ◽  
Ewing’S Sarcoma ◽  
Ewing's Sarcoma ◽  
Ets Transcription Factors ◽  
Downstream Target

scholarly journals Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors

2010 ◽  
Vol 162 (3) ◽  
pp. 625-631 ◽  
Author(s):  
Jonna Salonen ◽  
Ewa Rajpert-De Meyts ◽  
Susanna Mannisto ◽  
John E Nielsen ◽  
Niels Graem ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Germ Cell ◽  
Germ Cells ◽  
Target Genes ◽  
Developmental Expression ◽  
Human Testis ◽  
Testicular Development ◽  
Downstream Target ◽  
Germ Cell Differentiation

ObjectiveTesticular germ cell cancer is the most common malignancy among young males. The pre-invasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms.MethodsFetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Müllerian hormone/Müllerian-inhibiting substance (AMH), and inhibin-α (INHα).ResultsGATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHα and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative.ConclusionsDifferential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.

scholarly journals Nuclear Factor-κB-inducing Kinase (NIK) Contains an Amino-terminal Inhibitor of Apoptosis (IAP)-binding Motif (IBM) That Potentiates NIK Degradation by Cellular IAP1 (c-IAP1)

2014 ◽  
Vol 289 (44) ◽  
pp. 30680-30689 ◽  
Author(s):  
Sunhee Lee ◽  
Madhavi Challa-Malladi ◽  
Shawn B. Bratton ◽  
Casey W. Wright
Keyword(s):  
Target Genes ◽  
Tumor Necrosis Factor Receptor ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Binding Motif ◽  
The Novel ◽  
Amino Terminal ◽  
Close Proximity ◽  
The Stability ◽  
And Function

Activation of the noncanonical NF-κB pathway hinges on the stability of the NF-κB-inducing kinase (NIK), which is kept at low levels basally by a protein complex consisting of the E3 ubiquitin ligases cellular inhibitor of apoptosis 1 and 2 (c-IAP1/2) proteins and the tumor necrosis factor receptor-associated factors 2 and 3 (TRAF2/3). NIK is brought into close proximity to the c-IAPs through a TRAF2-TRAF3 bridge where TRAF2 recruits c-IAP1/2 and TRAF3 binds to NIK. However, it is not clear how the c-IAPs specifically recognize and ubiquitylate NIK in the complex. We have identified an IAP-binding motif (IBM) at the amino terminus of NIK. IBMs are utilized by a number of proapoptotic proteins to antagonize IAP function. Here, we utilize mutational studies to demonstrate that wild-type NIK is destabilized in the presence of c-IAP1, whereas the NIK IBM mutant is stable. NIK interacts with the second baculovirus IAP repeat (BIR2) domain of c-IAP1 via the IBM, and this interaction, in turn, provides substrate recognition for c-IAP1 mediated ubiquitylation and degradation of NIK. Furthermore, in the presence of the NIK IBM mutant, we observed an elevated processing of p100 to p52 followed by increased expression of NF-κB target genes. Together, these findings reveal the novel identification and function of the NIK IBM, which promotes c-IAP1-dependent ubiquitylation of NIK, resulting in optimal NIK turnover to ensure that noncanonical NF-κB signaling is off in the absence of an activating signal.

Abstract 392: Decreased ARNT Mediates Cardiovascular Endothelial Dysfunction in Diabetic Cardiomyopathy

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Maura Knapp ◽  
Mei Zheng ◽  
Hao Huang ◽  
James K Liao ◽  
Rongxue Wu
Keyword(s):  
Endothelial Dysfunction ◽  
Diabetic Cardiomyopathy ◽  
Target Genes ◽  
Cardiac Metabolism ◽  
Tube Formation ◽  
No Production ◽  
Protein Levels ◽  
Endothelial Tube Formation ◽  
High Fat Chow

Background: Endothelial dysfunction is thought to be one of the key risk factors leading to cardiac dysfunction. We have previously shown that ARNT is a critical regulator of cardiac metabolism and its deletion in the heart mimics diabetic cardiomyopathy. Here, we hypothesize that reduced ARNT expression in the endothelium may lead to endothelial dysfunction and contribute to diabetic cardiomyopathy. Methods and Results: Primary cardiac endothelial cells (mCVEC) were isolated from DB/DB mouse hearts and confirmed using vWF staining and flow cytometry. Isolated mCVEC from DB/DB mice showed more than a 50% reduction in ARNT protein levels, suggesting that endothelial ARNT may play a role in diabetic hearts. We generated a mouse with an endothelial specific ARNT deletion (ecARNT -/- ) by crossing ARNT flox/flox mice with Cre recombinase mice under the control of the VE-Cadherin promoter. Deletion of ARNT in the endothelium was achieved by the administration of oral tamoxifen chow. ecARNT -/- mice displayed cardiac hypertrophy and worsened cardiac function after high-fat chow feeding. In vitro studies were done using siRNA technology to knockdown ARNT in mCVEC. Knockdown of ARNT did not increase cell viability at base level, but led to impaired capillary-like endothelial tube formation and reduced cell migration in response to high glucose treatment. Nitric oxide (NO) production (a marker of endothelial dysfunction) and eNOS expression were also reduced after ARNT knockdown. To determine the underlying mechanisms by which ARNT may regulate endothelial metabolism we performed a DNA microarray and confirmed our results using RT-PCR. We discovered a significant induction of NF-kB and its target genes, including ELAM-1 and ICAM-1. These changes are similar to those we observed in mCVEC from DB/DB mouse hearts. Taken together, this data shows that a reduction in ARNT may regulate endothelial dysfunction in the diabetic heart through an inflammatory pathway. Conclusion: Endothelial ARNT may be a critical mediator of endothelial function and could serve as a therapeutic target for diabetic cardiomyopathy.

scholarly journals Serum lipoprotein–derived fatty acids regulate hypoxia-inducible factor

2020 ◽  
Vol 295 (52) ◽  
pp. 18284-18300
Author(s):  
Wei Shao ◽  
Jiwon Hwang ◽  
Chune Liu ◽  
Debaditya Mukhopadhyay ◽  
Shan Zhao ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Transcription Factors ◽  
Target Genes ◽  
Cultured Cells ◽  
Cell Metabolism ◽  
Control Cell ◽  
Hypoxia Inducible Factor ◽  
Mitochondrial Respiratory Chain ◽  
Serum Lipoprotein ◽  
Downstream Target

Oxygen regulates hypoxia-inducible factor (HIF) transcription factors to control cell metabolism, erythrogenesis, and angiogenesis. Whereas much has been elucidated about how oxygen regulates HIF, whether lipids affect HIF activity is un-known. Here, using cultured cells and two animal models, we demonstrate that lipoprotein-derived fatty acids are an independent regulator of HIF. Decreasing extracellular lipid supply inhibited HIF prolyl hydroxylation, leading to accumulation of the HIFα subunit of these heterodimeric transcription factors comparable with hypoxia with activation of downstream target genes. The addition of fatty acids to culture medium suppressed this signal, which required an intact mitochondrial respiratory chain. Mechanistically, fatty acids and oxygen are distinct signals integrated to control HIF activity. Finally, we observed lipid signaling to HIF and changes in target gene expression in developing zebrafish and adult mice, and this pathway operates in cancer cells from a range of tissues. This study identifies fatty acids as a physiological modulator of HIF, defining a mechanism for lipoprotein regulation that functions in parallel to oxygen.

scholarly journals Histone demethylase KDM5C is a SAHA-sensitive central hub at the crossroads of transcriptional axes involved in multiple neurodevelopmental disorders

2019 ◽  
Vol 28 (24) ◽  
pp. 4089-4102 ◽  
Author(s):  
Loredana Poeta ◽  
Agnese Padula ◽  
Benedetta Attianese ◽  
Mariaelena Valentino ◽  
Lucia Verrillo ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Neurodevelopmental Disorders ◽  
Target Genes ◽  
Downstream Target ◽  
Deacetylase Inhibitor ◽  
Core Feature ◽  
Genes Encoding ◽  
Vitro Analysis ◽  
In Vitro Analysis

Abstract A disproportional large number of neurodevelopmental disorders (NDDs) is caused by variants in genes encoding transcription factors and chromatin modifiers. However, the functional interactions between the corresponding proteins are only partly known. Here, we show that KDM5C, encoding a H3K4 demethylase, is at the intersection of transcriptional axes under the control of three regulatory proteins ARX, ZNF711 and PHF8. Interestingly, mutations in all four genes (KDM5C, ARX, ZNF711 and PHF8) are associated with X-linked NDDs comprising intellectual disability as a core feature. in vitro analysis of the KDM5C promoter revealed that ARX and ZNF711 function as antagonist transcription factors that activate KDM5C expression and compete for the recruitment of PHF8. Functional analysis of mutations in these genes showed a correlation between phenotype severity and the reduction in KDM5C transcriptional activity. The KDM5C decrease was associated with a lack of repression of downstream target genes Scn2a, Syn1 and Bdnf in the embryonic brain of Arx-null mice. Aiming to correct the faulty expression of KDM5C, we studied the effect of the FDA-approved histone deacetylase inhibitor suberanilohydroxamic acid (SAHA). In Arx-KO murine ES-derived neurons, SAHA was able to rescue KDM5C depletion, recover H3K4me3 signalling and improve neuronal differentiation. Indeed, in ARX/alr-1-deficient Caenorhabditis elegans animals, SAHA was shown to counteract the defective KDM5C/rbr-2-H3K4me3 signalling, recover abnormal behavioural phenotype and ameliorate neuronal maturation. Overall, our studies indicate that KDM5C is a conserved and druggable effector molecule across a number of NDDs for whom the use of SAHA may be considered a potential therapeutic strategy.

scholarly journals Use of Differentiating Adult Stem Cells (Marrow Stromal Cells) to Identify New Downstream Target Genes for Transcription Factors

Stem Cells ◽  
2006 ◽  
Vol 24 (3) ◽  
pp. 642-652 ◽  
Author(s):  
Joni Ylöstalo ◽  
Jason R. Smith ◽  
Radhika R. Pochampally ◽  
Robert Matz ◽  
Ichiro Sekiya ◽  
...  
Keyword(s):  
Stem Cells ◽  
Transcription Factors ◽  
Stromal Cells ◽  
Adult Stem Cells ◽  
Target Genes ◽  
Marrow Stromal Cells ◽  
Downstream Target

scholarly journals Homeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motif

2000 ◽  
Vol 14 (4) ◽  
pp. 435-451 ◽  
Author(s):  
Stéphane Germain ◽  
Michael Howell ◽  
Graeme M. Esslemont ◽  
Caroline S. Hill
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Expression Patterns ◽  
Common Mechanism ◽  
Homeodomain Proteins ◽  
Promoter Elements ◽  
Winged Helix ◽  
Effector Domain ◽  
Dna Binding Specificity ◽  
Necessary And Sufficient

We have investigated the regulation of the activin-inducible distal element (DE) of the Xenopus goosecoid promoter. The results show that paired-like homeodomain transcription factors of the Mix family, Mixer and Milk, but not Mix.1, mediate activin/TGF-β-induced transcription through the DE by interacting with the effector domain of Smad2, thereby recruiting active Smad2/Smad4 complexes to the Mixer/Milk-binding site. We identify a short motif in the carboxyl termini of Mixer and Milk, which is demonstrated to be both necessary and sufficient for interaction with the effector domain of Smad2 and is required for mediating activin/TGF-β-induced transcription. This motif is not confined to these homeodomain proteins, but is also present in the Smad2-interacting winged-helix proteins Xenopus Fast-1, human Fast-1, and mouse Fast-2. We demonstrate directly that transcription factors of different DNA-binding specificity recruit activated Smads to distinct promoter elements via a common mechanism. These observations, together with the temporal and spatial expression patterns ofMixer and Milk, lead us to propose a model for mesoendoderm formation in Xenopus in which these homeodomain transcription factor/Smad complexes play a role in initiating and maintaining transcription of target genes in response to endogenous activin-like signals.

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