Increased cAMP in Monocytes Augments Notch Signaling Mechanisms by Elevating RBP-J and Transducin-like Enhancer of Split (TLE)

ABSTRACT The Notch receptor is involved in many cell fate determination events in vertebrates and invertebrates. It has been shown inDrosophila melanogaster that Delta-dependent Notch signaling activates the transcription factor Suppressor of Hairless, leading to an increased expression of the Enhancer of Splitgenes. Genetic evidence has also implicated the kuzbaniangene, which encodes a disintegrin metalloprotease, in the Notch signaling pathway. By using a two-cell coculture assay, we show here that vertebrate Dl-1 activates the Notch-1 cascade. Consistent with previous data obtained with active forms of Notch-1 aHES-1-derived promoter construct is transactivated in cells expressing Notch-1 in response to Dl-1 stimulation. Impairing the proteolytic maturation of the full-length receptor leads to a decrease in HES-1 transactivation, further supporting the hypothesis that only mature processed Notch is expressed at the cell surface and activated by its ligand. Furthermore, we observed that Dl-1-inducedHES-1 transactivation was dependent both on Kuzbanian and RBP-J activities, consistent with the involvement of these two proteins in Notch signaling in Drosophila. We also observed that exposure of Notch-1-expressing cells to Dl-1 results in an increased level of endogenous HES-1 mRNA. Finally, coculture of Dl-1-expressing cells with myogenic C2 cells suppresses differentiation of C2 cells into myotubes, as previously demonstrated for Jagged-1 and Jagged-2, and also leads to an increased level of endogenousHES-1 mRNA. Thus, Dl-1 behaves as a functional ligand for Notch-1 and has the same ability to suppress cell differentiation as the Jagged proteins do.

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Notch signaling and its integration with other signaling mechanisms

Regenerative Medicine ◽

10.2217/17460751.1.2.195 ◽

2006 ◽

Vol 1 (2) ◽

pp. 195-205 ◽

Cited By ~ 22

Author(s):

Cecilia Sahlgren ◽

Urban Lendahl

Keyword(s):

Notch Signaling ◽

Signaling Mechanisms

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The Notch Pathway Intermediate HES-1 Silences CD4 Gene Expression

Molecular and Cellular Biology ◽

10.1128/mcb.18.12.7166 ◽

1998 ◽

Vol 18 (12) ◽

pp. 7166-7175 ◽

Cited By ~ 61

Author(s):

Han K. Kim ◽

Gerald Siu

Keyword(s):

Gene Expression ◽

T Cell ◽

Notch Signaling ◽

Signaling Pathway ◽

Transcriptional Control ◽

Notch Pathway ◽

Notch Signaling Pathway ◽

Thymic Development ◽

Enhancer Function ◽

Enhancer Of Split

ABSTRACT We have previously identified a transcriptional silencer that is critical for proper expression of the CD4 gene during T-cell development. Here we report that the Hairy/Enhancer of Split homologue HES-1, a transcription factor in the lin12/Notch signaling pathway, binds to an important functional site in the CD4 silencer. Overexpression of HES-1 leads to the silencer site-dependent repression of CD4 promoter and enhancer function as well as the downregulation of endogenous CD4 expression in CD4+ CD8−TH cells. Interestingly, overexpression of an activated form of Notch1 (NotchIC) leads to the repression of CD4 promoter and enhancer function both in the presence and absence of the silencer. NotchIC-mediated CD4 silencer function is not affected by the deletion of the HES-1-binding site, indicating that multiple factors binding to CD4 transcriptional control elements are responsive to signaling from this pathway, including other silencer-binding factors. Taken together, these data are consistent with the hypothesis that the lin12/Notch signaling pathway is important in thymic development and provide a molecular mechanism via the control of CD4 gene expression in which the lin12/Notch pathway affects T-cell developmental fate.

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Notch-IGF1 signaling during liver regeneration drives biliary epithelial cell expansion and inhibits hepatocyte differentiation

Science Signaling ◽

10.1126/scisignal.aay9185 ◽

2021 ◽

Vol 14 (688) ◽

pp. eaay9185

Author(s):

Sarah E. Minnis-Lyons ◽

Sofía Ferreira-González ◽

Niya Aleksieva ◽

Tak Yung Man ◽

Victoria L. Gadd ◽

...

Keyword(s):

Notch Signaling ◽

Large Scale ◽

Biliary Epithelial Cell ◽

Hepatocyte Differentiation ◽

Adult Liver ◽

Chronic Liver Injury ◽

Hepatocyte Regeneration ◽

Signaling Mechanisms ◽

Mammalian Liver ◽

Notch Inhibition

In the adult liver, a population of facultative progenitor cells called biliary epithelial cells (BECs) proliferate and differentiate into cholangiocytes and hepatocytes after injury, thereby restoring liver function. In mammalian models of chronic liver injury, Notch signaling is essential for bile duct formation from these cells. However, the continual proliferation of BECs and differentiation of hepatocytes in these models have limited their use for determining whether Notch signaling is required for BECs to replenish hepatocytes after injury in the mammalian liver. Here, we used a temporally restricted model of hepatic repair in which large-scale hepatocyte injury and regeneration are initiated through the acute loss of Mdm2 in hepatocytes, resulting in the rapid, coordinated proliferation of BECs. We found that transient, early activation of Notch1- and Notch3-mediated signaling and entrance into the cell cycle preceded the phenotypic expansion of BECs into hepatocytes. Notch inhibition reduced BEC proliferation, which resulted in failure of BECs to differentiate into hepatocytes, indicating that Notch-dependent expansion of BECs is essential for hepatocyte regeneration. Notch signaling increased the abundance of the insulin-like growth factor 1 receptor (IGF1R) in BECs, and activating IGFR signaling increased BEC numbers but suppressed BEC differentiation into hepatocytes. These results suggest that different signaling mechanisms control BEC expansion and hepatocyte differentiation.

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Aspartyl-asparagyl β hydroxylase over-expression in human hepatoma is linked to activation of insulin-like growth factor and notch signaling mechanisms

Hepatology ◽

10.1002/hep.21272 ◽

2006 ◽

Vol 44 (2) ◽

pp. 446-457 ◽

Cited By ~ 90

Author(s):

M. Chiara Cantarini ◽

Suzanne M. de la Monte ◽

Maoyin Pang ◽

Ming Tong ◽

Antonia D'Errico ◽

...

Keyword(s):

Growth Factor ◽

Notch Signaling ◽

Insulin Like Growth Factor ◽

Human Hepatoma ◽

Over Expression ◽

Signaling Mechanisms

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Notch Signaling Induces Rapid Degradation of Achaete-Scute Homolog 1

Molecular and Cellular Biology ◽

10.1128/mcb.22.9.3129-3139.2002 ◽

2002 ◽

Vol 22 (9) ◽

pp. 3129-3139 ◽

Cited By ~ 104

Author(s):

Virote Sriuranpong ◽

Michael W. Borges ◽

Christopher L. Strock ◽

Eric K. Nakakura ◽

D. Neil Watkins ◽

...

Keyword(s):

Notch Signaling ◽

Neural Development ◽

Transcriptional Repression ◽

Bhlh Protein ◽

Bhlh Transcription Factor ◽

Small Cell Lung ◽

Rapid Degradation ◽

Helix Loop Helix ◽

Initial Appearance ◽

Enhancer Of Split

ABSTRACT In neural development, Notch signaling plays a key role in restricting neuronal differentiation, promoting the maintenance of progenitor cells. Classically, Notch signaling causes transactivation of Hairy-enhancer of Split (HES) genes which leads to transcriptional repression of neural determination and differentiation genes. We now report that in addition to its known transcriptional mechanism, Notch signaling also leads to rapid degradation of the basic helix-loop-helix (bHLH) transcription factor human achaete-scute homolog 1 (hASH1). Using recombinant adenoviruses expressing active Notch1 in small-cell lung cancer cells, we showed that the initial appearance of Notch1 coincided with the loss of hASH1 protein, preceding the full decay of hASH1 mRNA. Overexpression of HES1 alone was capable of down-regulating hASH1 mRNA but could not replicate the acute reduction of hASH1 protein induced by Notch1. When adenoviral hASH1 was coinfected with Notch1, we still observed a dramatic and abrupt loss of the exogenous hASH1 protein, despite high levels of ongoing hASH1 RNA expression. Notch1 treatment decreased the apparent half-life of the adenoviral hASH1 protein and increased the fraction of hASH1 which was polyubiquitinylated. The proteasome inhibitor MG132 reversed the Notch1-induced degradation. The Notch RAM domain was dispensable but a lack of the OPA and PEST domains inactivated this Notch1 action. Overexpression of the hASH1-dimerizing partner E12 could protect hASH1 from degradation. This novel function of activated Notch to rapidly degrade a class II bHLH protein may prove to be important in many contexts in development and in cancer.

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Antagonism of notch signaling activity by members of a novel protein family encoded by the bearded and enhancer of split gene complexes

Development ◽

10.1242/dev.127.2.291 ◽

2000 ◽

Vol 127 (2) ◽

pp. 291-306 ◽

Cited By ~ 8

Author(s):

E.C. Lai ◽

R. Bodner ◽

J. Kavaler ◽

G. Freschi ◽

J.W. Posakony

Keyword(s):

Notch Signaling ◽

Cell Fate ◽

Notch Pathway ◽

Notch Receptor ◽

Principal Mechanism ◽

Cell Fate Decisions ◽

Amino Terminal ◽

Small Proteins ◽

High Affinity Binding Site ◽

Enhancer Of Split

Cell-cell signaling through the Notch receptor is a principal mechanism underlying cell fate specification in a variety of developmental processes in metazoans, such as neurogenesis. In this report we describe our investigation of seven members of a novel gene family in Drosophila with important connections to Notch signaling. These genes all encode small proteins containing predicted basic amphipathic (α)-helical domains in their amino-terminal regions, as described originally for Bearded; accordingly, we refer to them as Bearded family genes. Five members of the Bearded family are located in a newly discovered gene complex, the Bearded Complex; two others reside in the previously identified Enhancer of split Complex. All members of this family contain, in their proximal upstream regions, at least one high-affinity binding site for the Notch-activated transcription factor Suppressor of Hairless, suggesting that all are directly regulated by the Notch pathway. Consistent with this, we show that Bearded family genes are expressed in a variety of territories in imaginal tissue that correspond to sites of active Notch signaling. We demonstrate that overexpression of any family member antagonizes the activity of the Notch pathway in multiple cell fate decisions during adult sensory organ development. These results suggest that Bearded family genes encode a novel class of effectors or modulators of Notch signaling.

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A Human Protein with Sequence Similarity to DrosophilaMastermind Coordinates the Nuclear Form of Notch and a CSL Protein To Build a Transcriptional Activator Complex on Target Promoters

Molecular and Cellular Biology ◽

10.1128/mcb.21.13.4337-4346.2001 ◽

2001 ◽

Vol 21 (13) ◽

pp. 4337-4346 ◽

Cited By ~ 76

Author(s):

Motoo Kitagawa ◽

Toshinao Oyama ◽

Taichi Kawashima ◽

Barry Yedvobnick ◽

Anumeha Kumar ◽

...

Keyword(s):

Notch Signaling ◽

Signaling Pathway ◽

Mammalian Cells ◽

Sequence Similarity ◽

Notch Signaling Pathway ◽

Dominant Negative ◽

Intracellular Domain ◽

Human Sequence ◽

Pathway Expression ◽

Enhancer Of Split

ABSTRACT Mastermind (Mam) has been implicated as an important positive regulator of the Notch signaling pathway by genetic studies usingDrosophila melanogaster. Here we describe a biochemical mechanism of action of Mam within the Notch signaling pathway. Expression of a human sequence related to Drosophila Mam (hMam-1) in mammalian cells augments induction of Hairy Enhancer of split (HES) promoters by Notch signaling. hMam-1 stabilizes and participates in the DNA binding complex of the intracellular domain of human Notch1 and a CSL protein. Truncated versions of hMam-1 that can maintain an association with the complex behave in a dominant negative fashion and depress transactivation. Furthermore,Drosophila Mam forms a similar complex with the intracellular domain of Drosophila Notch andDrosophila CSL protein during activation of Enhancer of split, the Drosophila counterpart ofHES. These results indicate that Mam is an essential component of the transcriptional apparatus of Notch signaling.

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Secreted forms of DELTA and SERRATE define antagonists of Notch signaling in Drosophila

Development ◽

10.1242/dev.124.17.3439 ◽

1997 ◽

Vol 124 (17) ◽

pp. 3439-3448 ◽

Cited By ~ 14

Author(s):

X. Sun ◽

S. Artavanis-Tsakonas

Keyword(s):

Notch Signaling ◽

Molecular Level ◽

Notch Pathway ◽

Dominant Negative ◽

Genetic Interactions ◽

Wing Margin ◽

Loss Of Function ◽

Dominant Negative Mutations ◽

Notch Ligands ◽

Enhancer Of Split

We examined the function of secreted forms of the two known Drosophila Notch ligands, DELTA and SERRATE, by expressing them under various promoters in the Drosophila developing eye and wing. The phenotypes associated with the expression of secreted Delta (DlS) or secreted Serrate (SerS) forms mimic loss-of-function mutations in the Notch pathway. Both genetic interactions between DlS or SerS transgenics and duplications or loss-of-function mutations of Delta or Serrate indicate that DlS and SerS behave as dominant negative mutations. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split mdelta, a target of Notch signaling, is down-regulated by SERS. The antagonistic nature of the two mutant secreted ligand forms in the eye is consistent with their behavior in the wing, where they are capable of down-regulating wing margin specific genes opposite to the effects of the endogenous ligands. This analysis uncovers secreted molecular antagonists of Notch signaling and provides evidence of qualitative differences in the actions of the two ligands DLS and SERS.

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