Functional conservation of mouse Notch receptor family members

Katô, H.; Sakai, Takashi; Tamura, Kaori; Minoguchi, Shigeru; Shirayoshi, Yasuaki; Hamada, Y.; Tsujimoto, Yoshihide; Honjo, Tasuku

doi:10.1016/0014-5793(96)01046-0

Cited by 90 publications

(77 citation statements)

References 25 publications

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“…This difference likely relates to the presence of a C-terminal autonomous transactivation domain in the NICD-1, which acts independently of RBP-J. Such a transactivation domain sequence is absent in the NICD-4, and consequently, it requires RBP-J to initiate transcription (35). Therefore, the reduced induction capacity of NICD-4 is likely related to the number of RBP-J that are present in the shortened Ϫ2616 and Ϫ1587 DLL4 promoter fragments.…”

Section: Discussionmentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

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The DELTA like-4 ligand (DLL4) belongs to the highly conserved NOTCH family and is specifically expressed in the endothelium. DLL4 regulates crucial processes in vascular growth, including endothelial cell (EC) sprouting and arterial specification. Its expression is increased by VEGF-A. In the present study, we show that VEGF-induced DLL4 expression depends on NOTCH activation. VEGF-induced DLL4 expression was prevented by the blockage of NOTCH signaling with ␥-secretase or ADAM inhibitors in human cardiac microvascular ECs. Similar to VEGF-A, recombinant DLL4 itself stimulated NOTCH signaling and resulted in up-regulation of DLL4, suggesting a positive feed-forward mechanism. These effects were abrogated by NOTCH inhibitors but not by inhibition of VEGF signaling. NOTCH activation alone suffices to induce DLL4 expression as illustrated by the positive effect of NOTCH intracellular domain (NICD)-1 or -4 overexpression. To discriminate between NICD/RBP-J and FOXC2-regulated DLL4 expression, DLL4 promoter activity was assessed in promoter deletion experiments. NICD induced promoter activity was dependent on RBP-J site but independent of the FOXC2 binding site. Accordingly, constitutively active FOXC2 did not affect DLL4 expression. The notion that the positive feed-forward mechanism might propagate NOTCH activation to neighboring ECs was supported by our observation that DLL4-eGFP-transfected ECs induced DLL4 expression in nontransfected cells in their vicinity. In summary, our data provide evidence for a mechanism by which VEGF or ligand-induced NOTCH signaling up-regulates DLL4 through a positive feedforward mechanism. By this mechanism, DLL4 could propagate its own expression and enable synchronization of NOTCH expression and signaling between ECs.The NOTCH family encompasses a fundamental signaling pathway involving four receptors (NOTCH-1, -2, -3, and -4) and, in vertebrates, five cognate ligands (DLL-1, -3, and -4, and JAGGED-1 and -2). Cell-cell contact is a prerequisite for NOTCH signaling as all members are membrane bound. The first activation step upon receptor-ligand interaction involves cleavage of the extracellular domain of the NOTCH receptor by ADAM (a disintegrin and metalloprotease). Subsequently, the ␥-secretase complex instigates a second proteolytic cleavage resulting in the release of the NOTCH intracellular domain (NICD) 2 into the cytoplasm. Next, the NICD translocates to the nucleus, where it associates with the Recombinant signal binding protein for immunoglobulin kappa J region (RBP-J) CBF1/RBP-J, Su(H), Lag1 (CSL) transcription factor to initiate the transcription of its downstream targets basic helix-loop-helix proteins HES (hairy/enhancer of split) and hairy related transcription factors (HRT, HEY, and

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Section: Discussionmentioning

confidence: 99%

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Caolo

Akker

Verbruggen

et al. 2010

Journal of Biological Chemistry

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“…Mammalian members of the Notch family of proteins interact with the DNA binding protein RBP-J, and the resulting complex usually behaves as a transcriptional activator (Kato et al, 1996;Artavanis-Tsakonas et al, 1999). To examine the possibility that the NICD1/RBP-J complex functions as a transcriptional repressor for p27 and p57 genes, we crossed Fbxw7 F/F mice with Rbpj F/F mice (Han et al, 2002), and then generated Fbxw7…”

Section: Kip1mentioning

confidence: 99%

Complex regulation of cell-cycle inhibitors by Fbxw7 in mouse embryonic fibroblasts

et al. 2009

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The F-box protein Fbxw7 (also known as Fbw7, SEL-10, hCdc4 or hAgo) mediates the ubiquitylation and thereby contributes to the degradation of proteins that positively regulate cell cycle. Conditional ablation of Fbxw7 in mouse embryonic fibroblasts (MEFs) induces cell-cycle arrest accompanied by abnormal accumulation of the intracellular domain of Notch1 (NICD1) and c-Myc. However, the molecular mechanisms by which the accumulation of NICD1 and c-Myc induces cell-cycle arrest have remained unclear. We have now examined the expression of cell-cycle inhibitors in Fbxw7-deficient MEFs and found that the abundance of p27Kip1 and p57Kip2 is paradoxically decreased. This phenomenon appears to be attributable to the accumulation of NICD1, given that it was recapitulated by overexpression of NICD1 and blocked by ablation of RBP-J. Conversely, the expression of p16Ink4a and p19 ARF was increased in an NICD1-independent manner in Fbxw7-null MEFs. The increased expression of p19 ARF was recapitulated by overexpression of c-Myc and abolished by ablation of c-Myc, suggesting that the accumulation of c-Myc is primarily responsible for that of p19 ARF . In contrast, the upregulation of p16Ink4a appeared to be independent of c-Myc. These results indicate that cell-cycle inhibitors undergo complex regulation by the Fbxw7-mediated proteolytic system.

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“…The recombination signal binding protein for immunoglobulin kappa J region gene (Rbpj) encodes the transcriptional regulator protein RBPjκ (hereafter referred to simply as RBPJ), which controls multiple cellular processes in response to ligand-induced activation of all NOTCH receptors (Kato et al, 1996). In the absence of NOTCH receptor activation, RBPJ acts as a transcriptional repressor, but when bound to the activated and nuclear-localized intracellular domain of the NOTCH receptor (NICD), RBPJ acts as a transcriptional activator at promoters containing RBPJ-binding sites (Kato et al, 1996). Mice that are conditionally deficient in Rbpj or NOTCH signaling-related genes show a multitude of deficits in proper tissue and organ development and maintenance, which is in general due to improper control of cell proliferation and differentiation.…”

Section: Introductionmentioning

confidence: 99%

RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche

et al. 2014

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Stem cells are influenced by their surrounding microenvironment, or niche. In the testis, Sertoli cells are the key niche cells directing the population size and differentiation fate of spermatogonial stem cells (SSCs). Failure to properly regulate SSCs leads to infertility or germ cell hyperplasia. Several Sertoli cell-expressed genes, such as Gdnf and Cyp26b1, have been identified as being indispensable for the proper maintenance of SSCs in their niche, but the pathways that modulate their expression have not been identified. Although we have recently found that constitutively activating NOTCH signaling in Sertoli cells leads to premature differentiation of all prospermatogonia and sterility, suggesting that there is a crucial role for this pathway in the testis stem cell niche, a true physiological function of NOTCH signaling in Sertoli cells has not been demonstrated. To this end, we conditionally ablated recombination signal binding protein for immunoglobulin kappa J region (Rbpj), a crucial mediator of NOTCH signaling, in Sertoli cells using Amh-cre. Rbpj knockout mice had: significantly increased testis sizes; increased expression of niche factors, such as Gdnf and Cyp26b1; significant increases in the number of pre-and post-meiotic germ cells, including SSCs; and, in a significant proportion of mice, testicular failure and atrophy with tubule lithiasis, possibly due to these unsustainable increases in the number of germ cells. We also identified germ cells as the NOTCH ligand-expressing cells. We conclude that NOTCH signaling in Sertoli cells is required for proper regulation of the testis stem cell niche and is a potential feedback mechanism, based on germ cell input, that governs the expression of factors that control SSC proliferation and differentiation.

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Functional conservation of mouse Notch receptor family members

Cited by 90 publications

References 25 publications

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Feed-forward Signaling by Membrane-bound Ligand Receptor Circuit

Complex regulation of cell-cycle inhibitors by Fbxw7 in mouse embryonic fibroblasts

RBPJ in mouse Sertoli cells is required for proper regulation of the testis stem cell niche

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