Functional relationships between Notch, Su(H) and the bHLH genes of the E(spl) complex: the E(spl) genes mediate only a subset of Notch activities during imaginal development

Development ◽  
1996 ◽  
Vol 122 (9) ◽  
pp. 2719-2728 ◽  
Author(s):  
J.F. de Celis ◽  
J. de Celis ◽  
P. Ligoxygakis ◽  
A. Preiss ◽  
C. Delidakis ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Functional Relationships ◽  
Helix Loop Helix ◽  
Suppressor Of Hairless ◽  
Bhlh Genes ◽  
Enhancer Of Split ◽  
Notch Activation

The basic helix-loop-helix proteins of the Enhancer of split complex constitute a link between activation of the transmembrane receptor Notch and the resulting effects on transcription of downstream genes. The Suppressor of Hairless protein is the intermediary between Notch activation and expression of all Enhancer of split genes even though individual genes have distinct patterns of expression in imaginal discs. A comparison between the phenotypes produced by Notch, Suppressor of Hairless and Enhancer of split mutations in the wing and thorax indicate that Suppressor of Hairless and Notch requirements are indistinguishable, but that Enhancer of split activity is only essential for a subset of developmental processes involving Notch function. Likewise, the ectopic expression of Enhancer of split proteins does not reproduce all the consequences typical of ectopic Notch activation. We suggest that the Notch pathway bifurcates after the activation of Suppressor of Hairless and that Enhancer of split activity is not required when the consequence of Notch function is the transcriptional activation of downstream genes. Transcriptional activation mediated by Suppressor of Hairless and transcriptional repression mediated by Enhancer of split could provide greater diversity in the response of individual genes to Notch activity.

scholarly journals Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 465-471 ◽  
Author(s):  
AN Goldfarb ◽  
K Lewandowska
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Cellular Differentiation ◽  
Interaction Analysis ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Protein Product ◽  
Monocytic Differentiation ◽  
E Proteins ◽  
Helix Loop Helix

In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forced overexpression of SCL/tal can block monocytic differentiation of M1 murine myeloid leukemia cells. Thus, inappropriate expression of wild- type SCL/tal protein may in part account for the maturation arrest phenotype observed in T-ALL cells. In this study, ectopic expression of the SCL/tal gene blocked the differentiation of C2C12 muscle precursor cells. Characterization of the mechanism of differentiation blockade showed that the SCL/tal protein repressed transcriptional activation by the myogenic bHLH factor MyoD. Protein interaction analysis showed that SCL/tal and MyoD compete for common partners (E bHLH proteins) but do not directly bind one other. A model is thus proposed in which ectopic SCL/tal protein, by its ability to titrate out E proteins, prevents the formation of bHLH complexes that drive cellular differentiation: the “Id-like” mechanism.

scholarly journals Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism

Blood ◽  
1995 ◽  
Vol 85 (2) ◽  
pp. 465-471 ◽  
Author(s):  
AN Goldfarb ◽  
K Lewandowska
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Cellular Differentiation ◽  
Interaction Analysis ◽  
Lymphoblastic Leukemia ◽  
Ectopic Expression ◽  
Protein Product ◽  
Monocytic Differentiation ◽  
E Proteins ◽  
Helix Loop Helix

Abstract In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forced overexpression of SCL/tal can block monocytic differentiation of M1 murine myeloid leukemia cells. Thus, inappropriate expression of wild- type SCL/tal protein may in part account for the maturation arrest phenotype observed in T-ALL cells. In this study, ectopic expression of the SCL/tal gene blocked the differentiation of C2C12 muscle precursor cells. Characterization of the mechanism of differentiation blockade showed that the SCL/tal protein repressed transcriptional activation by the myogenic bHLH factor MyoD. Protein interaction analysis showed that SCL/tal and MyoD compete for common partners (E bHLH proteins) but do not directly bind one other. A model is thus proposed in which ectopic SCL/tal protein, by its ability to titrate out E proteins, prevents the formation of bHLH complexes that drive cellular differentiation: the “Id-like” mechanism.

Abstract P221: Retinoblastoma Protein--Associated Proteins 48 and 46 Are Novel p300/GATA4-Binding Partners Involved in Hypertrophic Responses in Cardiomyocytes

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Yoichi Sunagawa ◽  
Yasufumi Katanasaka ◽  
Taishi Terada ◽  
Yuichi Watanabe ◽  
Hiromichi Wada ◽  
...  
Keyword(s):  
Transcriptional Activation ◽  
Transcriptional Repression ◽  
Zinc Finger Protein ◽  
Retinoblastoma Protein ◽  
Histone Deacetylation ◽  
Hek293 Cells ◽  
Functional Protein ◽  
Nucleosome Remodeling ◽  
Transcriptional Activation Domain ◽  
Functional Relationships

Background: A zinc finger protein GATA4 is one of hypertrophy-responsive transcription factors, and increases its DNA-binding and transcriptional activities in response to hypertrophic stimuli in cardiomyocytes. Activation of GATA4 during this process is mediated, in part, through acetylation by intrinsic histone acetyltransferases such as a transcriptional coactivator p300. Here, we show that retinoblastoma protein (Rb)-associated protein 48 and 46 (RbAp48, RbAp46), components of NuRD (nucleosome remodeling and deacetylase) complex that has been implicated in chromatin remodeling and transcriptional repression associated with histone deacetylation, are novel components of p300/GATA4 complex. However, the precise functional relationships among p300, GATA4, RbAp48, and RbAp46 remain unknown. Methods and Results: A series of GST pull-down assays revealed that the C-terminal domain of RbAp48/46 bound to the N-terminal transcriptional activation domain of GATA4 and C/H-3 domain of p300, respectively. Immunoprecipitation followed by western blotting demonstrated that RbAp48/46 repressed p300-induced acetylation of GATA4 and histones. While overexpressions of RbAp48/46 inhibited p300/GATA4-induced atrial natriuretic factors (ANF) and endotheline-1 (ET-1) promoter activities, knockdown of neither RbAp48 nor RbAp46 by RNAi enhanced these promoter activities in HEK293 cells. Stimulation of cardiomyocytes with phenylephrine (PE) decreased the binding of GATA4/p300 with RbAp48/46. RbAp48/46 repressed PE-induced hypertrophic responses such as myofibrillar organization, increase in cell size and promoter activation of the ANF and ET-1 in cardiomyocytes. Conclusion: These findings demonstrate that RbAp48 and RbAp46 form a functional protein complex with GATA4/p300 and regulated hypertrophic responses in cardiomyocytes.

scholarly journals Notch Activation Is an Early and Critical Event during T-Cell Leukemogenesis in Ikaros-Deficient Mice

2006 ◽  
Vol 26 (1) ◽  
pp. 209-220 ◽  
Author(s):  
Alexis Dumortier ◽  
Robin Jeannet ◽  
Peggy Kirstetter ◽  
Eva Kleinmann ◽  
MacLean Sellars ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Suppressor ◽  
Target Gene ◽  
Critical Role ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Target Gene ◽  
Target Gene Expression ◽  
T Cell Leukemogenesis ◽  
Notch Activation

ABSTRACT The Ikaros transcription factor is both a key regulator of lymphocyte differentiation and a tumor suppressor in T lymphocytes. Mice carrying a hypomorphic mutation (IkL/L) in the Ikaros gene all develop thymic lymphomas. IkL/L tumors always exhibit strong activation of the Notch pathway, which is required for tumor cell proliferation in vitro. Notch activation occurs early in tumorigenesis and may precede transformation, as ectopic expression of the Notch targets Hes-1 and Deltex-1 is detected in thymocytes from young IkL/L mice with no overt signs of transformation. Notch activation is further amplified by secondary mutations that lead to C-terminal truncations of Notch 1. Strikingly, restoration of Ikaros activity in tumor cells leads to a rapid and specific downregulation of Notch target gene expression and proliferation arrest. Furthermore, Ikaros binds to the Notch-responsive element in the Hes-1 promoter and represses Notch-dependent transcription from this promoter. Thus, Ikaros-mediated repression of Notch target gene expression may play a critical role in defining the tumor suppressor function of this factor.

Atonal, rough and the resolution of proneural clusters in the developing Drosophila retina

Development ◽  
1996 ◽  
Vol 122 (12) ◽  
pp. 4139-4147 ◽  
Author(s):  
M.E. Dokucu ◽  
S.L. Zipursky ◽  
R.L. Cagan
Keyword(s):  
Transcription Factor ◽  
Cluster Formation ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Helix Loop Helix ◽  
Eye Disc ◽  
Bhlh Factors ◽  
Specific Regulation ◽  
Photoreceptor Neurons ◽  
Proneural Cluster

In the developing Drosophila retina, the proneural gene for photoreceptor neurons is atonal, a basic helix-loop-helix transcription factor. Using atonal as a marker for proneural maturation, we examine the stepwise resolution of proneural clusters during the initiation of ommatidial differentiation in the developing eye disc. In addition, evidence is provided that atonal is negatively regulated by rough, a homeobox-containing transcription factor expressed exclusively in the retina. This interaction leads to the refinement of proneural clusters to specify R8, the first neuron to emerge in the retinal neuroepithelium. Ectopic expression of atonal or removal of rough results in the transformation of a discrete ‘equivalence group’ of cells into R8s. In addition, ectopic expression of rough blocks atonal expression and proneural cluster formation within the morphogenetic furrow. Thus, rough provides retina-specific regulation to the more general atonal-mediated proneural differentiation pathway. The opposing roles of atonal and rough are not mediated through the Notch pathway, as their expression remains complementary when Notch activity is reduced. These observations suggest that homeobox-containing genes can provide tissue-specific regulation to bHLH factors.

Ectopic expression of cyclin D1 prevents activation of gene transcription by myogenic basic helix-loop-helix regulators

1994 ◽  
Vol 14 (8) ◽  
pp. 5259-5267
Author(s):  
S S Rao ◽  
C Chu ◽  
D S Kohtz
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Gene Transcription ◽  
Transcriptional Activation ◽  
Ectopic Expression ◽  
Binding Motif ◽  
Dependent Manner ◽  
Basic Helix Loop Helix ◽  
Helix Loop Helix ◽  
Muscle Gene

Activation of muscle gene transcription in differentiating skeletal myoblasts requires their withdrawal from the cell cycle. The effects of ectopic cyclin expression on activation of muscle gene transcription by myogenic basic helix-loop-helix (bHLH) regulators were investigated. Ectopic expression of cyclin D1, but not cyclins A, B1, B2, C, D3, and E, inhibited transcriptional activation of muscle gene reporter constructs by myogenic bHLH regulators in a dose-dependent manner. Ectopic expression of cyclin D1 inhibited the activity of a myogenic bHLH regulator mutant lacking the basic region protein kinase C site, indicating that phosphorylation of this site is not relevant to the mechanism of inhibition. Analysis of cyclin D1 mutants revealed that the C-terminal acidic region was required for inhibition of myogenic bHLH regulator activity, whereas an intact N-terminal pRb binding motif was not essential. Together, these results implicate expression of cyclin D1 as a central determinant of a putatively novel mechanism that links positive control of cell cycle progression to negative regulation of genes expressed in differentiated myocytes.

Thylacine 1 is expressed segmentally within the paraxial mesoderm of the Xenopus embryo and interacts with the Notch pathway

Development ◽  
1998 ◽  
Vol 125 (11) ◽  
pp. 2041-2051 ◽  
Author(s):  
D.B. Sparrow ◽  
W.C. Jen ◽  
S. Kotecha ◽  
N. Towers ◽  
C. Kintner ◽  
...  
Keyword(s):  
Expression Patterns ◽  
Ectopic Expression ◽  
Notch Pathway ◽  
Notch Signalling ◽  
Xenopus Embryo ◽  
Paraxial Mesoderm ◽  
Marker Genes ◽  
Transcription Activator ◽  
Presomitic Mesoderm ◽  
Helix Loop Helix

The presomitic mesoderm of vertebrates undergoes a process of segmentation in which cell-cell interactions mediated by the Notch family of receptors and their associated ligands are involved. The vertebrate homologues of Drosophila Δ are expressed in a dynamic, segmental pattern within the presomitic mesoderm, and alterations in the function of these genes leads to a perturbed pattern of somite segmentation. In this study we have characterised Thylacine 1 which encodes a basic helix-loop-helix class transcription activator. Expression of Thylacine is restricted to the presomitic mesoderm, localising to the anterior half of several somitomeres in register with domains of X-Delta-2 expression. Ectopic expression of Thylacine in embryos causes segmentation defects similar to those seen in embryos in which Notch signalling is altered, and these embryos also show severe disruption in the expression patterns of the marker genes X-Delta-2 and X-ESR5 within the presomitic mesoderm. Finally, the expression of Thylacine is altered in embryos when Notch signalling is perturbed. These observations suggest strongly that Thylacine 1 has a role in the segmentation pathway of the Xenopus embryo, by interacting with the Notch signalling pathway.

A subset of notch functions during Drosophila eye development require Su(H) and the E(spl) gene complex

Development ◽  
1998 ◽  
Vol 125 (15) ◽  
pp. 2893-2900 ◽  
Author(s):  
P. Ligoxygakis ◽  
S.Y. Yu ◽  
C. Delidakis ◽  
N.E. Baker
Keyword(s):  
Cell Fate ◽  
Notch Pathway ◽  
Signal Transduction Pathway ◽  
Notch Signalling ◽  
Transduction Pathway ◽  
Notch Signalling Pathway ◽  
Bhlh Genes ◽  
Drosophila Eye ◽  
Enhancer Of Split ◽  
Signalling Process

The Notch signalling pathway is involved in many processes where cell fate is decided. Previous work showed that Notch is required at successive steps during R8 specification in the Drosophila eye. Initially, Notch enhances atonal expression and promotes atonal function. After atonal autoregulation has been established, Notch signalling represses atonal expression during lateral specification. In this paper we investigate which known components of the Notch pathway are involved in each signalling process. Using clonal analysis we show that a ligand of Notch, Delta, is required along with Notch for both proneural enhancement and lateral specification, while the downstream components Suppressor-of-Hairless and Enhancer-of-Split are involved only in lateral specification. Our data point to a distinct signal transduction pathway during proneural enhancement by Notch. Using misexpression experiments we also show that particular Enhancer-of-split bHLH genes can differ greatly in their contribution to lateral specification.

scholarly journals Hes6 Promotes Cortical Neurogenesis and Inhibits Hes1 Transcription Repression Activity by Multiple Mechanisms

2003 ◽  
Vol 23 (19) ◽  
pp. 6922-6935 ◽  
Author(s):  
Michel-Olivier Gratton ◽  
Elena Torban ◽  
Stephanie Belanger Jasmin ◽  
Francesca M. Theriault ◽  
Michael S. German ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Cortical Neurons ◽  
Transcriptional Repression ◽  
Protein Kinase Ck2 ◽  
Molecular Mechanisms ◽  
Neural Progenitor Cells ◽  
Helix Loop Helix ◽  
Molecular Events ◽  
Kinase Ck2 ◽  
Enhancer Of Split

ABSTRACT Hes1 is a mammalian basic helix-loop-helix transcriptional repressor that inhibits neuronal differentiation together with corepressors of the Groucho (Gro)/Transducin-like Enhancer of split (TLE) family. The interaction of Hes1 with Gro/TLE is mediated by a WRPW tetrapeptide present in all Hairy/Enhancer of split (Hes) family members. In contrast to Hes1, the related protein Hes6 promotes neuronal differentiation. Little is known about the molecular mechanisms that underlie the neurogenic activity of Hes6. It is shown here that Hes6 antagonizes Hes1 function by two mechanisms. Hes6 inhibits the interaction of Hes1 with its transcriptional corepressor Gro/TLE. Moreover, it promotes proteolytic degradation of Hes1. This effect is maximal when both Hes1 and Hes6 contain the WRPW motif and is reduced when Hes6 is mutated to eliminate a conserved site (Ser183) that can be phosphorylated by protein kinase CK2. Consistent with these findings, Hes6 inhibits Hes1-mediated transcriptional repression in cortical neural progenitor cells and promotes the differentiation of cortical neurons, a process that is normally inhibited by Hes1. Mutation of Ser183 impairs the neurogenic ability of Hes6. Taken together, these findings clarify the molecular events underlying the neurogenic function of Hes6 and suggest that this factor can antagonize Hes1 activity by multiple mechanisms.

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