PMID- 12414908
OWN - NLM
STAT- MEDLINE
DCOM- 20021209
LR  - 20161124
IS  - 0021-972X (Print)
IS  - 0021-972X (Linking)
VI  - 87
IP  - 11
DP  - 2002 Nov
TI  - PAX3/forkhead homolog in rhabdomyosarcoma oncoprotein activates glucose 
      transporter 4 gene expression in vivo and in vitro.
PG  - 5312-24
AB  - Increased levels of glucose uptake and increased expression of the glucose 
      transporter (GLUT) genes are characteristic features of tumors. In the 
      muscle-derived tumor alveolar rhabdomyosarcoma (ARMS), a chromosomal 
      translocation t(2:13) generates the PAX3/forkhead homolog in rhabdomyosarcoma 
      (FKHR) oncoprotein. In muscle tissues, glucose transport is primarily mediated by 
      GLUT4. However, the mechanisms that regulate GLUT4 gene expression in tumor 
      tissues are largely unknown. Therefore, we evaluated the role of PAX3/FKHR in the 
      regulation of GLUT4 gene expression in muscle tumorigenesis. GLUT4 mRNA and 
      protein were detected in ARMS-derived human biopsies and in ARMS-derived RH30 
      myoblasts, which both express the PAX3/FKHR chimeric protein, but not in either 
      C2C12 or embryonal rhabdomyosarcoma-derived myoblasts. GLUT4 was functionally 
      active in RH30 cells, because insulin induced a 1.4-fold stimulation of basal 
      2-deoxyglucose uptake rates. Coexpression of PAX3/FKHR increased basal 
      transcriptional activity from a GLUT4 promoter reporter (GLUT4-P) in C2C12, 
      SaOS-2, and Chinese hamster ovary-K1 cells in a dose-dependent and 
      tissue-specific manner. PAX3/FKHR mutants with deletions in either the 
      homeodomain (DeltaHD) or the FKHR-derived activation domain (DeltaFKHR), or in 
      which the PAX3-derived paired domain (PD) was point-mutated (PD-R56L), were 
      unable to activate GLUT4-P. Progressive 5'-deletion analysis of GLUT4-P further 
      identified a specific region of the promoter, -66/+163 bp, which retained about 
      65% of the full transactivation effect. EMSA studies established that the 
      PAX3/FKHR protein directly and specifically binds to this region and to a shorter 
      fragment, -4/+36 bp, that contains potential binding sites for HD and PD, but not 
      to a -4/+36-bp fragment whose HD and PD sites have been mutated. Thus, the 
      functional interaction of PAX3/FKHR with GLUT4-P appears to require all of the 
      functional domains of PAX3/FKHR, as well as a -4/+36-bp region within the GLUT4 
      promoter. Taken together, the data suggest that the GLUT4 gene is a downstream 
      target of PAX3/FKHR and that GLUT4 is aberrantly transactivated by this 
      oncoprotein both in vivo and in vitro.
FAU - Armoni, Michal
AU  - Armoni M
AD  - Institute of Endocrinology, Diabetes and Metabolism, Rambam Medical Center, 
      Technion-Israel Institute of Technology, Haifa 31096, Israel. 
      amichal@tx.technion.ac.il
FAU - Quon, Michael J
AU  - Quon MJ
FAU - Maor, Gila
AU  - Maor G
FAU - Avigad, Smadar
AU  - Avigad S
FAU - Shapiro, David N
AU  - Shapiro DN
FAU - Harel, Chava
AU  - Harel C
FAU - Esposito, Diana
AU  - Esposito D
FAU - Goshen, Yaacov
AU  - Goshen Y
FAU - Yaniv, Isaac
AU  - Yaniv I
FAU - Karnieli, Eddy
AU  - Karnieli E
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - J Clin Endocrinol Metab
JT  - The Journal of clinical endocrinology and metabolism
JID - 0375362
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (FOXO1 protein, human)
RN  - 0 (Forkhead Box Protein O1)
RN  - 0 (Forkhead Transcription Factors)
RN  - 0 (Foxo1 protein, mouse)
RN  - 0 (Glucose Transporter Type 4)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Muscle Proteins)
RN  - 0 (PAX4 protein, human)
RN  - 0 (Paired Box Transcription Factors)
RN  - 0 (Pax4 protein, mouse)
RN  - 0 (SLC2A4 protein, human)
RN  - 0 (Slc2a4 protein, mouse)
RN  - 0 (Transcription Factors)
RN  - EC 1.13.12.- (Luciferases)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Blotting, Northern
MH  - CHO Cells
MH  - Cell Line
MH  - Cricetinae
MH  - DNA-Binding Proteins/genetics/*physiology
MH  - Fibroblasts/metabolism
MH  - Forkhead Box Protein O1
MH  - Forkhead Transcription Factors
MH  - *Gene Expression
MH  - Glucose/metabolism
MH  - Glucose Transporter Type 4
MH  - Homeodomain Proteins/genetics/*physiology
MH  - Humans
MH  - Luciferases/genetics
MH  - Mice
MH  - Monosaccharide Transport Proteins/*genetics
MH  - *Muscle Proteins
MH  - Muscles/metabolism
MH  - Paired Box Transcription Factors
MH  - Promoter Regions, Genetic
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Rhabdomyosarcoma, Alveolar/genetics
MH  - Transcription Factors/genetics/*physiology
MH  - Transcriptional Activation
MH  - Transfection
MH  - Tumor Cells, Cultured
EDAT- 2002/11/05 04:00
MHDA- 2002/12/10 04:00
CRDT- 2002/11/05 04:00
PHST- 2002/11/05 04:00 [pubmed]
PHST- 2002/12/10 04:00 [medline]
PHST- 2002/11/05 04:00 [entrez]
AID - 10.1210/jc.2002-020318 [doi]
PST - ppublish
SO  - J Clin Endocrinol Metab. 2002 Nov;87(11):5312-24. doi: 10.1210/jc.2002-020318.