Induction of ID2 expression by hypoxia-inducible factor-1: ARole in dedifferentiation of hypoxic neuroblastoma cells.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/125849
- author
- Löfstedt, Tobias LU ; Jögi, Annika LU ; Sigvardsson, Mikael LU ; Gradin, Katarina ; Poellinger, Lorenz ; Påhlman, Sven LU and Axelson, Håkan LU
- organization
- publishing date
- 2004
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Biological Chemistry
- volume
- 279
- issue
- 38
- pages
- 39223 - 39231
- publisher
- American Society for Biochemistry and Molecular Biology
- external identifiers
-
- wos:000223791500006
- scopus:4544361863
- pmid:15252039
- ISSN
- 1083-351X
- DOI
- 10.1074/jbc.M402904200
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Molecular Medicine (013031200), Hematopoietic Stem Cell Laboratory (013022012), Department of Translational Medicine (013017500)
- id
- f4e2b5e6-140b-4369-bd06-d0d369cf5ca4 (old id 125849)
- alternative location
- http://www.jbc.org/cgi/content/abstract/M402904200v1
- date added to LUP
- 2016-04-01 12:35:28
- date last changed
- 2022-07-30 05:13:28
@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 = {{American Society for Biochemistry and Molecular Biology}},
series = {{Journal of Biological Chemistry}},
title = {{Induction of ID2 expression by hypoxia-inducible factor-1: ARole in dedifferentiation of hypoxic neuroblastoma cells.}},
url = {{https://lup.lub.lu.se/search/files/2985870/624056.pdf}},
doi = {{10.1074/jbc.M402904200}},
volume = {{279}},
year = {{2004}},
}