scholarly journals The bHLH-Zip transcription factor Tfeb is essential for placental vascularization

Development ◽  
1998 ◽  
Vol 125 (23) ◽  
pp. 4607-4616 ◽  
Author(s):  
E. Steingrimsson ◽  
L. Tessarollo ◽  
S.W. Reid ◽  
N.A. Jenkins ◽  
N.G. Copeland
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Critical Role ◽  
Cell Types ◽  
Targeted Disruption ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Related Family ◽  
Low Levels

Tfeb is a member of the basic Helix-Loop-Helix-Zipper family of transcription factors. In vitro studies have shown that TFEB can bind DNA as a homodimer or as a heterodimer with three closely related family members: MITF, TFE3 and TFEC. While mutations of Mitf have been shown to affect the development of a number of cell types including melanocytes, osteoclasts, and masts cells, little is known about the phenotypic consequences of mutations at Tfe3, Tfeb and Tfec. Here we show that mice with a targeted disruption of Tfeb die between 9.5 and 10.5 days in embryonic development and have severe defects in placental vascularization. Tfeb is expressed at low levels in the embryo but at high levels in the labyrinthine trophoblast cells of the placenta. While labyrinthine cells are present in the mutant Tfeb placenta, they fail to express VEGF, a potent mitogen required for normal vasculogenesis of the embryo and extraembryonic tissues. In Tfeb mutant embryos the embryonic vasculature forms normally but few vessels are seen entering the placenta and those that do enter fail to thrive and branch normally. Our results indicate that Tfeb plays a critical role in the signal transduction processes required for normal vascularization of the placenta.

scholarly journals Phosphorylation of E47 as a potential determinant of B-cell-specific activity.

1996 ◽  
Vol 16 (12) ◽  
pp. 6900-6908 ◽  
Author(s):  
S R Sloan ◽  
C P Shen ◽  
R McCarrick-Walmsley ◽  
T Kadesch
Keyword(s):  
B Cells ◽  
Dna Binding ◽  
B Cell ◽  
B Lymphocyte ◽  
Specific Activity ◽  
Cell Types ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Potential Determinant

The E2A gene encodes two basic helix-loop-helix proteins designated E12 and E47. Although these proteins are widely expressed, they are required only for the B-lymphocyte lineage where DNA binding is mediated distinctively by E47 homodimers. By studying the properties of deltaE47, an N-terminal truncation of E47, we provide evidence that phosphorylation may contribute to B-cell-specific DNA binding by E47. Two serines N terminal to the deltaE47 basic helix-loop-helix domain were found to be phosphorylated in a variety of cell types but were hypophosphorylated in B cells. Phosphorylating these serines in vitro inhibited DNA binding by deltaE47 homodimers but not by deltaE47-containing heterodimers, such as deltaE47:MyoD. These results argue that hypophosphorylation may be a prerequisite for activity of E47 homodimers in B cells, suggesting the use of an inductive (nonstochastic) step in early B-cell development.

The basic-helix-loop-helix protein pod1 is critically important for kidney and lung organogenesis

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5771-5783 ◽  
Author(s):  
S.E. Quaggin ◽  
L. Schwartz ◽  
S. Cui ◽  
P. Igarashi ◽  
J. Deimling ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Perinatal Period ◽  
Branching Morphogenesis ◽  
Bhlh Transcription Factor ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Kidney Morphogenesis

Epithelial-mesenchymal interactions are required for the development of all solid organs but few molecular mechanisms that underlie these interactions have been identified. Pod1 is a basic-helix-loop-helix (bHLH) transcription factor that is highly expressed in the mesenchyme of developing organs that include the lung, kidney, gut and heart and in glomerular visceral epithelial cells (podocytes). To determine the function of Pod1 in vivo, we have generated a lacZ-expressing null Pod1 allele. Null mutant mice are born but die in the perinatal period with severely hypoplastic lungs and kidneys that lack alveoli and mature glomeruli. Although Pod1 is exclusively expressed in the mesenchyme and podocytes, major defects are observed in the adjacent epithelia and include abnormalities in epithelial differentiation and branching morphogenesis. Pod1 therefore appears to be essential for regulating properties of the mesenchyme that are critically important for lung and kidney morphogenesis. Defects specific to later specialized cell types where Pod1 is expressed, such as the podocytes, were also observed, suggesting that this transcription factor may play multiple roles in kidney morphogenesis.

scholarly journals Orphan Nuclear Receptor Small Heterodimer Partner, a Novel Corepressor for a Basic Helix-Loop-Helix Transcription Factor BETA2/NeuroD

2004 ◽  
Vol 18 (4) ◽  
pp. 776-790 ◽  
Author(s):  
Joon-Young Kim ◽  
Khoi Chu ◽  
Han-Jong Kim ◽  
Hyun-A Seong ◽  
Ki-Cheol Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Nuclear Receptor ◽  
Transcriptional Activity ◽  
Orphan Nuclear Receptor ◽  
Small Heterodimer Partner ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
E Box ◽  
Coactivator P300

Abstract Small heterodimer partner (SHP; NR0B2) is an atypical orphan nuclear receptor that lacks a conventional DNA binding domain (DBD) and represses the transcriptional activity of various nuclear receptors. In this study, we examined the novel cross talk between SHP and BETA2/NeuroD, a basic helix-loop-helix transcription factor. In vitro and in vivo protein interaction studies showed that SHP physically interacts with BETA2/NeuroD, but not its heterodimer partner E47. Moreover, confocal microscopic study and immunostaining results demonstrated that SHP colocalized with BETA2 in islets of mouse pancreas. SHP inhibited BETA2/NeuroD-dependent transactivation of an E-box reporter, whereas SHP was unable to repress the E47-mediated transactivation and the E-box mutant reporter activity. In addition, SHP repressed the BETA2-dependent activity of glucokinase and cyclin-dependent kinase inhibitor p21 gene promoters. Gel shift and in vitro protein competition assays indicated that SHP inhibits neither dimerization nor DNA binding of BETA2 and E47. Rather, SHP directly repressed BETA2 transcriptional activity and p300-enhanced BETA2/NeuroD transcriptional activity by inhibiting interaction between BETA2 and coactivator p300. We also showed that C-terminal repression domain within SHP is also required for BETA2 repression. However, inhibition of BETA2 activity was not observed by naturally occurring human SHP mutants that cannot interact with BETA2/NeuroD. Taken together, these results suggest that SHP acts as a novel corepressor for basic helix-loop-helix transcription factor BETA2/NeuroD by competing with coactivator p300 for binding to BETA2/NeuroD and by its direct transcriptional repression function.

scholarly journals Targeting the Microphthalmia Basic Helix-Loop-Helix–Leucine Zipper Transcription Factor to a Subset of E-Box Elements In Vitro and In Vivo

1998 ◽  
Vol 18 (12) ◽  
pp. 6930-6938 ◽  
Author(s):  
I. Aksan ◽  
C. R. Goding
Keyword(s):  
Transcription Factor ◽  
Leucine Zipper ◽  
Pigment Cells ◽  
Specific Gene ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
P Gene ◽  
E Box

ABSTRACT The development of melanocytes, which are pigment-producing cells responsible for skin, hair, and eye color, is absolutely dependent on the action of the microphthalmia basic helix-loop-helix–leucine zipper (bHLH-LZ) transcription factor (Mi); mice lacking a functional Mi protein are entirely devoid of pigment cells. Mi has been shown to activate transcription of the tyrosinase,TRP-1, TRP-2, and QNR-71 genes through specific E-box elements, most notably the highly conserved M box. We investigated the mechanism which enables Mi to be recruited specifically to a restricted subset of E boxes in target promoters while being prevented from binding E-box elements in other promoters. We show both in vitro and in vivo that the presence of a T residue flanking a CATGTG E box is an essential determinant of the ability of Mi to bind DNA, and we successfully predict that the CATGTG E box from the P gene would not bind Mi. In contrast, no specific requirement for the sequences flanking a CACGTG E box was observed, and no binding to an atypical E box in the c-Kit promoter was detected. The relevance of these observations to the control of melanocyte-specific gene expression was highlighted by the fact that the E-box elements located in thetyrosinase, TRP-1, TRP-2, andQNR-71 promoters without exception possess a 5′ flanking T residue which is entirely conserved between species as diverse as man and turtle. The ability of Mi to discriminate between different E-box motifs provides a mechanism to restrict the repertoire of genes which are likely to be regulated by Mi and provides insight into the ability of bHLH-LZ transcription factors to achieve the specificity required for the precise coordination of transcription during development.

scholarly journals The PAX6 gene is activated by the basic helix–loop–helix transcription factor NeuroD/BETA2

2003 ◽  
Vol 376 (3) ◽  
pp. 707-715 ◽  
Author(s):  
Eleonora MARSICH ◽  
Amedeo VETERE ◽  
Matteo DI PIAZZA ◽  
Gianluca TELL ◽  
Sergio PAOLETTI
Keyword(s):  
Transcription Factor ◽  
Pax6 Gene ◽  
Mobility Shift ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Dna Binding Sites ◽  
E Boxes ◽  
Nih 3T3 ◽  
Electrophoretic Mobility Shift Assays

PAX6 is a transcription factor that plays an important role during pancreatic morphogenesis. The aim of the present study is to identify the upstream activator(s) of the PAX6 gene possibly involved in the early stages of pancreatic differentiation. Recently, individual elements regulating PAX6 gene activity in the pancreas have been identified in a 1100 bp Spe/HincII fragment 4.6 kb upstream of exon 0. Preliminary sequence analysis of this region revealed some potential DNA-binding sites (E boxes) specific for the binding of basic helix–loop–helix transcription factors. By using electrophoretic mobility shift assays, we demonstrated that both nuclear protein extracts from insulin-secreting RINm5F cells and in vitro-translated NeuroD/BETA2 can bind specifically to these E boxes. Furthermore, by transient transfection experiments we demonstrated that the expression of basic helix–loop–helix transcription factor NeuroD/BETA2 can induce activation of the PAX6 promoter in the NIH-3T3 cell line. Thus we show that NeuroD/BETA2 is involved in the activation of the expression of PAX6 through E boxes in the PAX6 promoter localized in a 1.1 kb sequence within the 4.6 kb untranslated region upstream of exon 0.

Differential regulation of granulopoiesis by the basic helix-loop-helix transcriptional inhibitors Id1 and Id2

Blood ◽  
2005 ◽  
Vol 105 (11) ◽  
pp. 4272-4281 ◽  
Author(s):  
Miranda Buitenhuis ◽  
Hanneke W. M. van Deutekom ◽  
Liesbeth P. Verhagen ◽  
Anders Castor ◽  
Sten Eirik W. Jacobsen ◽  
...  
Keyword(s):  
Critical Role ◽  
Ectopic Expression ◽  
Constitutive Expression ◽  
Retroviral Transduction ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Cd34 Cells ◽  
Final Maturation ◽  
Inhibitor Of Dna Binding

Abstract Inhibitor of DNA binding (Id) proteins function as inhibitors of members of the basic helix-loop-helix family of transcription factors and have been demonstrated to play an important role in regulating lymphopoiesis. However, the role of these proteins in regulation of myelopoiesis is currently unclear. In this study, we have investigated the role of Id1 and Id2 in the regulation of granulopoiesis. Id1 expression was initially up-regulated during early granulopoiesis, which was then followed by a decrease in expression during final maturation. In contrast, Id2 expression was up-regulated in terminally differentiated granulocytes. In order to determine whether Id expression plays a critical role in regulating granulopoiesis, Id1 and Id2 were ectopically expressed in CD34+ cells by retroviral transduction. Our experiments demonstrate that constitutive expression of Id1 inhibits eosinophil development, whereas in contrast neutrophil differentiation was modestly enhanced. Constitutive Id2 expression accelerates final maturation of both eosinophils and neutrophils, whereas inhibition of Id2 expression blocks differentiation of both lineages. Transplantation of β2-microglobulin-/- nonobese diabetic severe combined immunodeficient (NOD/SCID) mice with CD34+ cells ectopically expressing Id1 resulted in enhanced neutrophil development, whereas ectopic expression of Id2 induced both eosinophil and neutrophil development. These data demonstrate that both Id1 and Id2 play a critical, although differential role in granulopoiesis.

scholarly journals The Basic Helix-Loop-Helix Transcription Factor Cph2 Regulates Hyphal Development in CandidaalbicansPartly via Tec1

2001 ◽  
Vol 21 (19) ◽  
pp. 6418-6428 ◽  
Author(s):  
Shelley Lane ◽  
Song Zhou ◽  
Ting Pan ◽  
Qian Dai ◽  
Haoping Liu
Keyword(s):  
Transcription Factor ◽  
Protein Kinase ◽  
Binding Sites ◽  
Regulatory Element ◽  
Ectopic Expression ◽  
Mitogen Activated Protein Kinase ◽  
Northern Analysis ◽  
Hyphal Development ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix

ABSTRACT Candida albicans undergoes a morphogenetic switch from budding yeast to hyphal growth form in response to a variety of stimuli and growth conditions. Multiple signaling pathways, including a Cph1-mediated mitogen-activated protein kinase pathway and an Efg1-mediated cyclic AMP/protein kinase A pathway, regulate the transition. Here we report the identification of a basic helix-loop-helix transcription factor of the Myc subfamily (Cph2) by its ability to promote pseudohyphal growth inSaccharomyces cerevisiae. Like sterol response element binding protein 1, Cph2 has a Tyr instead of a conserved Arg in the basic DNA binding region. Cph2 regulates hyphal development in C. albicans, ascph2/cph2 mutant strains show medium-specific impairment in hyphal development and in the induction of hypha-specific genes. However, many hypha-specific genes do not have potential Cph2 binding sites in their upstream regions. Interestingly, upstream sequences of all known hypha-specific genes are found to contain potential binding sites for Tec1, a regulator of hyphal development. Northern analysis shows that TEC1 transcription is highest in the medium in which cph2/cph2 displays a defect in hyphal development, and Cph2 is necessary for this transcriptional induction of TEC1. In vitro gel mobility shift experiments show that Cph2 directly binds to the two sterol regulatory element 1-like elements upstream of TEC1. Furthermore, the ectopic expression of TEC1 suppresses the defect ofcph2/cph2 in hyphal development. Therefore, the function of Cph2 in hyphal transcription is mediated, in part, through Tec1. We further show that this function of Cph2 is independent of the Cph1- and Efg1-mediated pathways.

scholarly journals Role for the Ran Binding Protein, Mog1p, in Saccharomyces cerevisiae SLN1-SKN7 Signal Transduction

2004 ◽  
Vol 3 (6) ◽  
pp. 1544-1556 ◽  
Author(s):  
Jade Mei-Yeh Lu ◽  
Robert J. Deschenes ◽  
Jan S. Fassler
Keyword(s):  
Signal Transduction ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Kinase Activity ◽  
Mitogen Activated Protein Kinase ◽  
Osmotic Response ◽  
Mitogen Activated Protein ◽  
Kinase Pathway

ABSTRACT Yeast Sln1p is an osmotic stress sensor with histidine kinase activity. Modulation of Sln1 kinase activity in response to changes in the osmotic environment regulates the activity of the osmotic response mitogen-activated protein kinase pathway and the activity of the Skn7p transcription factor, both important for adaptation to changing osmotic stress conditions. Many aspects of Sln1 function, such as how kinase activity is regulated to allow a rapid response to the continually changing osmotic environment, are not understood. To gain insight into Sln1p function, we conducted a two-hybrid screen to identify interactors. Mog1p, a protein that interacts with the yeast Ran1 homolog, Gsp1p, was identified in this screen. The interaction with Mog1p was characterized in vitro, and its importance was assessed in vivo. mog1 mutants exhibit defects in SLN1-SKN7 signal transduction and mislocalization of the Skn7p transcription factor. The requirement for Mog1p in normal localization of Skn7p to the nucleus does not fully account for the mog1-related defects in SLN1-SKN7 signal transduction, raising the possibility that Mog1p may play a role in Skn7 binding and activation of osmotic response genes.

scholarly journals Target gene selectivity of the myogenic basic helix–loop–helix transcription factor myogenin in embryonic muscle

2007 ◽  
Vol 311 (2) ◽  
pp. 650-664 ◽  
Author(s):  
Judith K. Davie ◽  
Jang-Hyeon Cho ◽  
Eric Meadows ◽  
Jesse M. Flynn ◽  
Jennifer R. Knapp ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Target Gene ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Embryonic Muscle
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