Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

Zheng, Xiaofeng; Linke, Sarah; Dias, José Maria Moreira; Zheng, Xiaowei; Gradin, Katarina; Wallis, Tristan P.; Hamilton, Brett; Gustafsson, Maria; Ruas, Jorge L.; Wilkins, Sarah E.; Bilton, Rebecca; Brismar, Kerstin; Whitelaw, Murray L.; Pereira, Teresa; Gorman, Jeffrey J.; Ericson, Johan; Peet, Daniel J.; Lendahl, Urban; Poellinger, Lorenz

doi:10.1073/pnas.0711591105

Cited by 234 publications

(255 citation statements)

References 19 publications

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“…It has been reported that the hypoxia inducible factor 1 (HIF-1) could augment Notch signaling during development (23,24). However, the role of Notch in the hypoxic tumor microenvironment has not been addressed.…”

Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

“…We speculate that increased N ICD levels through Jagged2 expression could reciprocally inhibit factor-inhibiting HIF (FIH) and augment HIF function to provide a hypoxic growth advantage independent of Notch target genes (30). Further evidence suggests that N ICD enhances HIF1 recruitment to its target gene promoters, resulting in increased HIF1 activity in vitro (23). HIF function would further increase the tumorigenicity of P493-6 as we have previously observed with P493-6 cells overexpressing a stabilized HIF-1 mutant (22).…”

Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

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Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Ectopic Myc expression plays a key role in human tumorigenesis, and Myc dose-dependent tumorigenesis has been well established in transgenic mice, but the Myc target genes that are dependent on Myc levels have not been well characterized. In this regard, we used the human P493-6 B cells, which have a preneoplastic state dependent on the Epstein–Barr viral EBNA2 protein and a neoplastic state with ectopic inducible Myc, to identify putative ectopic Myc target genes. Among the ectopic targets, JAG2 that encodes a Notch receptor ligand Jagged2, was directly induced by Myc. Inhibition of Notch signaling through RNAi targeting JAG2 or the γ-secretase Notch inhibitor N-[N-(3,5-difluorophenacetyl)-L-alanyl]-(S)-phenylglycine t-butyl ester (DAPT) preferentially inhibited the neoplastic state in vitro. Furthermore, P493-6 tumorigenesis was inhibited by DAPT in vivo. Ectopic expression of JAG2 did not enhance aerobic cell proliferation, but increased proliferation of hypoxic cells in vitro and significantly increased in vivo tumorigenesis. Furthermore, the expression of Jagged2 in P493-6 tumors often overlapped with regions of hypoxia. These observations suggest that Notch signaling downstream of Myc enables cells to adapt in the tumor hypoxic microenvironment.

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Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

Section: High Myc State Increases Notch Signaling Components With Jagmentioning

confidence: 99%

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Yustein¹,

Liu²,

Gao³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Several mechanisms have been proposed including direct icN1 stabilization by interaction with HIF proteins (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). As of yet, little attention has been given to Notch ligand regulation and the effects this may have on Notch activation under hypoxia.…”

Section: Introductionmentioning

confidence: 99%

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

Pietras

Stedingk

Lindgren

et al. 2011

Molecular Cancer Research

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Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on intracellular domain of the Notch1 receptor (icN1) stabilization by direct interaction with HIF proteins, little attention has been given to Notch ligand regulation during hypoxia. Here we show that the Notch ligand JAG2 is transcriptionally activated by hypoxia in a HIF-1a dependent manner. Hypoxic JAG2 induction resulted in elevated Notch activity in tumor cells, as was measured by increased icN1 levels and induction of the Notch target gene HEY1. In primary tumor material, JAG2 expression correlated with vascular development and angiogenesis gene signatures. In line with this, coculture experiments of endothelial cells with hypoxic breast cancer cells displayed a reduction in number of capillary-like tubes formed upon JAG2 siRNA treatment of the breast cancer cells. Together these results suggest that a hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells. Mol Cancer Res; 9(5); 626-36. Ó2011 AACR.

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“…Significantly, proteins containing the ankyrin repeat domain (ARD) such as Notch are other substrates for FIH-1 (8). Moreover, the binding affinity of FIH-1 for Notch 1 is appreciably greater than for HIF-1α (8,10). With respect to Notch 1, FIH-1 hydroxylates the Notch ICD at two asparagine residues (N 1945 and N 2012 ) (11).…”

mentioning

confidence: 99%

“…With respect to Notch 1, FIH-1 hydroxylates the Notch ICD at two asparagine residues (N 1945 and N 2012 ) (11). This has been shown to negatively regulate Notch activity in a myogenic cell line (10). Notch normally functions to maintain an undifferentiated state in this cell line, thus FIH-1's affect was to accelerate differentiation (10).…”

mentioning

confidence: 99%

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

Han¹,

Kaplan²,

Hamanaka

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

119

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Notch plays a critical role in the transition from proliferation to differentiation in the epidermis and corneal epithelium. Furthermore, aberrant Notch signaling is a feature of diseases like psoriasis, eczema, nonmelanoma skin cancer, and melanoma where differentiation and proliferation are impaired. Whereas much is known about the downstream events following Notch signaling, factors responsible for negatively regulating Notch receptor signaling after ligand activation are incompletely understood. Notch can undergo hydroxylation by factor-inhibiting hypoxia-inducible factor 1 (FIH-1); however, the biological significance of this phenomenon is unclear. Here we show that FIH-1 expression is upregulated in diseased epidermis and corneal epithelium. Elevating FIH-1 levels in primary human epidermal keratinocytes (HEKs) and human corneal epithelial keratinocytes (HCEKs) impairs differentiation in submerged cultures and in a "three-dimensional" organotypic raft model of human epidermis, in part, via a coordinate decrease in Notch signaling. Knockdown of FIH-1 enhances keratinocyte differentiation. Loss of FIH-1 in vivo increased Notch activity in the limbal epithelium, resulting in a more differentiated phenotype. microRNA-31 (miR-31) is an endogenous negative regulator of FIH-1 expression that results in keratinocyte differentiation, mediated by Notch activation. Ectopically expressing miR-31 in an undifferentiated corneal epithelial cell line promotes differentiation and recapitulates a corneal epithelium in a three-dimensional raft culture model. Our results define a previously unknown mechanism for keratinocyte fate decisions where Notch signaling potential is, in part, controlled through a miR-31/FIH-1 nexus.

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Interaction with factor inhibiting HIF-1 defines an additional mode of cross-coupling between the Notch and hypoxia signaling pathways

Cited by 234 publications

References 19 publications

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

Induction of ectopic Myc target gene JAG2 augments hypoxic growth and tumorigenesis in a human B-cell model

JAG2 Induction in Hypoxic Tumor Cells Alters Notch Signaling and Enhances Endothelial Cell Tube Formation

microRNA-31/factor-inhibiting hypoxia-inducible factor 1 nexus regulates keratinocyte differentiation

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