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JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation.

Pietras, Alexander LU ; von Stedingk, Kristoffer LU ; Lindgren, David LU ; Påhlman, Sven LU and Axelson, Håkan LU (2011) In Molecular Cancer Research 9. p.626-636
Abstract
Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on 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-1α 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, co-culture experiments of endothelial cells with hypoxic breast cancer cells... (More)
Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on 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-1α 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, co-culture 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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Cancer Research
volume
9
pages
626 - 636
publisher
American Association for Cancer Research
external identifiers
  • wos:000290610600010
  • pmid:21402725
  • scopus:79956010254
ISSN
1557-3125
DOI
10.1158/1541-7786.MCR-10-0508
language
English
LU publication?
yes
id
2c68df16-96ca-4698-99c0-ab4b97f34f73 (old id 1883964)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/21402725?dopt=Abstract
date added to LUP
2011-04-01 15:56:05
date last changed
2017-10-22 04:20:25
@article{2c68df16-96ca-4698-99c0-ab4b97f34f73,
  abstract     = {Several studies have revealed links between hypoxia and activation of Notch in solid tumors. While most reports have focused on 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-1α 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, co-culture 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.},
  author       = {Pietras, Alexander and von Stedingk, Kristoffer and Lindgren, David and Påhlman, Sven and Axelson, Håkan},
  issn         = {1557-3125},
  language     = {eng},
  pages        = {626--636},
  publisher    = {American Association for Cancer Research},
  series       = {Molecular Cancer Research},
  title        = {JAG2 induction in hypoxic tumor cells alters Notch signaling and enhances endothelial cell tube formation.},
  url          = {http://dx.doi.org/10.1158/1541-7786.MCR-10-0508},
  volume       = {9},
  year         = {2011},
}