PMID- 17374610
OWN - NLM
STAT- MEDLINE
DCOM- 20070628
LR  - 20210209
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 282
IP  - 19
DP  - 2007 May 11
TI  - Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator of the TrkB 
      neurotrophin receptor gene.
PG  - 14379-88
AB  - Neurotrophins and their cognate receptors play a pivotal role in the development 
      and function of the nervous system. High expression levels of the neurotrophin 
      receptor TrkB and its ligands in neuroblastomas are associated with an 
      unfavorable outcome. We report here that NTRK2, which encodes the TrkB receptor 
      tyrosine kinase, is an oxygen-regulated gene, whose expression is stimulated by 
      the hypoxia-inducible factor-1 (HIF-1). TrkB mRNA and protein levels were 
      elevated nearly 30-fold in neuroblastoma-derived Kelly cells in hypoxia (1% O(2)) 
      versus normoxia (21% O(2)). A luciferase reporter construct containing 
      approximately 2.1 kilobases of the human TrkB promoter was activated about 6-fold 
      both in hypoxia and after stimulation with the hypoxia mimetic 2,2'-dipyridyl 
      (100 microm) at 21% O(2). Luciferase activity in the presence of 2,2'-dipyridyl 
      was reduced significantly upon small interfering RNA knockdown of HIF-1alpha but 
      not of HIF-2alpha. Accordingly, hypoxia failed to stimulate the TrkB promoter in 
      mouse embryonic fibroblasts that lacked HIF-1alpha. The hypoxia-responsive 
      promoter region could be mapped to three HIF-1 binding elements that were located 
      between -923 and -879 bp relative to the transcription start site. The migration 
      of cultured neuroblastoma cells was increased approximately 2-fold upon 
      incubation at 1 versus 21% O(2). This effect of hypoxia was abrogated with the 
      tyrosine kinase inhibitor K252a (200 nm). Our findings indicate that 
      transcription of the NTRK2 gene is stimulated at low oxygen tension through a 
      HIF-1-dependent mechanism. In conclusion, enhanced expression of TrkB could 
      represent a critical switch for the previously reported dedifferentiation of 
      neuroblastoma cells under hypoxic conditions.
FAU - Martens, Lina K
AU  - Martens LK
AD  - Institut fur Vegetative Physiologie, Charite-Universitatsmedizin Berlin, Berlin, 
      Germany.
FAU - Kirschner, Karin M
AU  - Kirschner KM
FAU - Warnecke, Christina
AU  - Warnecke C
FAU - Scholz, Holger
AU  - Scholz H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070320
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Basic Helix-Loop-Helix Transcription Factors)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hif1a protein, mouse)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (RNA, Messenger)
RN  - 1B37H0967P (endothelial PAS domain-containing protein 1)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - Animals
MH  - Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism
MH  - Bone Neoplasms/metabolism/pathology
MH  - Cell Hypoxia
MH  - Cell Movement
MH  - Cells, Cultured
MH  - Chromatin Immunoprecipitation
MH  - Electrophoretic Mobility Shift Assay
MH  - Gene Expression Regulation
MH  - Humans
MH  - Hypoxia/*genetics/metabolism
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism/*physiology
MH  - Immunoenzyme Techniques
MH  - Kidney/metabolism/pathology
MH  - Mice
MH  - Mice, Knockout
MH  - Neuroblastoma/metabolism/pathology
MH  - Osteosarcoma/metabolism/pathology
MH  - Oxygen
MH  - Promoter Regions, Genetic
MH  - Protein Binding
MH  - RNA, Messenger/genetics/metabolism
MH  - Receptor, trkB/*genetics/metabolism
MH  - Response Elements
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Transcription, Genetic
MH  - Transcriptional Activation
EDAT- 2007/03/22 09:00
MHDA- 2007/06/29 09:00
CRDT- 2007/03/22 09:00
PHST- 2007/03/22 09:00 [pubmed]
PHST- 2007/06/29 09:00 [medline]
PHST- 2007/03/22 09:00 [entrez]
AID - S0021-9258(20)63741-3 [pii]
AID - 10.1074/jbc.M609857200 [doi]
PST - ppublish
SO  - J Biol Chem. 2007 May 11;282(19):14379-88. doi: 10.1074/jbc.M609857200. Epub 2007 
      Mar 20.