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Induction of ID2 expression by hypoxia-inducible factor-1: ARole in dedifferentiation of hypoxic neuroblastoma cells.

Löfstedt, Tobias LU ; Jögi, Annika LU ; Sigvardsson, Mikael LU ; Gradin, Katarina; Poellinger, Lorenz; Påhlman, Sven LU and Axelson, Håkan LU (2004) In Journal of Biological Chemistry 279(38). p.39223-39231
Abstract
ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by... (More)
ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at –725 and –1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors. (Less)
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author
organization
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Contribution to journal
publication status
published
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in
Journal of Biological Chemistry
volume
279
issue
38
pages
39223 - 39231
publisher
ASBMB
external identifiers
  • wos:000223791500006
  • scopus:4544361863
ISSN
1083-351X
DOI
10.1074/jbc.M402904200
language
English
LU publication?
yes
id
f4e2b5e6-140b-4369-bd06-d0d369cf5ca4 (old id 125849)
alternative location
http://www.jbc.org/cgi/content/abstract/M402904200v1
date added to LUP
2007-07-26 08:06:22
date last changed
2017-08-06 03:51:10
@article{f4e2b5e6-140b-4369-bd06-d0d369cf5ca4,
  abstract     = {ID (inhibitor of differentiation/DNA binding) proteins, frequently deregulated in advanced human malignancies, can participate in multiple fundamental traits of cancer, such as block of differentiation, increased proliferation, tissue invasiveness, and angiogenesis. We have previously demonstrated that hypoxia decreases expression of neuronal marker genes in neuroblastoma, but induces genes expressed in the neural crest, such as ID2. Because of its involvement in normal neural crest development and its ability to inhibit proneuronal bHLH proteins, the hypoxic induction of ID2 was of particular interest. Here we report fast induction kinetics of ID2 expression in hypoxic neuroblastoma cells. The up-regulation of ID2 was abolished by addition of actinomycin D, implicating a hypoxia-driven transcriptional mechanism. Analyzing the ID2 promoter revealed several potential binding sites for hypoxia-inducible factors. Subsequent electrophoretic mobility shift and chromatin immunoprecipitation assays demonstrated two functional HIF-1 binding sites within ID2 gene regulatory sequences located at –725 and –1893 relative to the transcriptional initiation point. In transfection assays, DNA constructs of the ID2 promoter, including the functional HIF-1 binding sites, induced luciferase reporter activity in a HIF-1-specific manner. These observations demonstrate that ID2 is actively engaged by hypoxia and represents a novel HIF-1 target. Hypoxia-induced ID2 expression could play a significant role in the previously observed dedifferentiation of hypoxic neuroblastoma cells, which in a clinical setting could lead to less mature and more aggressive tumors.},
  author       = {Löfstedt, Tobias and Jögi, Annika and Sigvardsson, Mikael and Gradin, Katarina and Poellinger, Lorenz and Påhlman, Sven and Axelson, Håkan},
  issn         = {1083-351X},
  language     = {eng},
  number       = {38},
  pages        = {39223--39231},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Induction of ID2 expression by hypoxia-inducible factor-1: ARole in dedifferentiation of hypoxic neuroblastoma cells.},
  url          = {http://dx.doi.org/10.1074/jbc.M402904200},
  volume       = {279},
  year         = {2004},
}