PMID- 12482504
OWN - NLM
STAT- MEDLINE
DCOM- 20030402
LR  - 20211203
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 30
IP  - 12
DP  - 2002 Dec
TI  - NF-kappaB plays a key role in hypoxia-inducible factor-1-regulated erythropoietin 
      gene expression.
PG  - 1419-27
AB  - OBJECTIVE: The aim of this study was to further define the signal transduction 
      pathways leading to hypoxia-inducible factor-1 (HIF-1) erythropoietin (EPO) gene 
      expression. MATERIALS AND METHODS: Human hepatocellular carcinoma cells (Hep3B) 
      were exposed to hypoxia (1% oxygen) and examined for mRNA expression, as well as 
      gene transactivation with RT-PCR and luciferase reporter gene assays, 
      respectively. RESULTS: Treatment with LY294002 (a selective pharmacological 
      inhibitor of phosphatidylinositol 3-kinase) significantly inhibited EPO protein 
      and mRNA expression in Hep3B cells exposed to hypoxia for 24 hours, while 
      treatment with PD098059 or SB203580 (selective pharmacological inhibitors of the 
      MEK and p38 mitogen-activated protein kinase pathways, respectively) had no 
      significant effects. The activity of AKT, a downstream target of PI3K, was 
      increased by hypoxia and was also inhibited by LY294002. Genetic inhibition of 
      AKT resulted in significant inhibition of NF-kappaB and HIF-1-mediated 
      transactivation, as well as EPO gene expression, in response to hypoxia. 
      Overexpression of constitutively active AKT resulted in increased NF-kappaB and 
      HIF-1 transactivation. The selective inhibitor of NF-kappaB, pyrrolidine 
      dithiocarbamate (PDTC), significantly blocked HIF-1 protein expression. 
      Inhibition of NF-kappaB with a superrepressor dominant negative IkappaBalpha 
      genetic construct also significantly blocked NF-kappaB and HIF-1 transactivation, 
      as well as EPO gene expression. CONCLUSION: We propose a key role for NF-kappaB 
      in EPO gene regulation in response to hypoxia.
FAU - Figueroa, Yanira G
AU  - Figueroa YG
AD  - Department of Pharmacology, Cancer Center, Tulane Health Sciences Center, 1430 
      Tulane Avenue, New Orleans, LA 70112, USA.
FAU - Chan, Anna K
AU  - Chan AK
FAU - Ibrahim, Rania
AU  - Ibrahim R
FAU - Tang, Yan
AU  - Tang Y
FAU - Burow, Matthew E
AU  - Burow ME
FAU - Alam, Jawed
AU  - Alam J
FAU - Scandurro, Aline B
AU  - Scandurro AB
FAU - Beckman, Barbara S
AU  - Beckman BS
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (NF-kappa B)
RN  - 0 (Nuclear Proteins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Transcription Factors)
RN  - 11096-26-7 (Erythropoietin)
RN  - EC 2.7.11.1 (AKT1 protein, human)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - DNA-Binding Proteins/biosynthesis/metabolism/*physiology
MH  - Erythropoietin/*genetics
MH  - Gene Expression Regulation/drug effects
MH  - Genes, Reporter
MH  - Humans
MH  - Hypoxia/metabolism
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - NF-kappa B/metabolism/*physiology
MH  - Nuclear Proteins/biosynthesis/metabolism/*physiology
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Protein Binding
MH  - *Protein Serine-Threonine Kinases
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/analysis/biosynthesis
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Signal Transduction
MH  - *Transcription Factors
MH  - Transcriptional Activation
MH  - Tumor Cells, Cultured
EDAT- 2002/12/17 04:00
MHDA- 2003/04/04 05:00
CRDT- 2002/12/17 04:00
PHST- 2002/12/17 04:00 [pubmed]
PHST- 2003/04/04 05:00 [medline]
PHST- 2002/12/17 04:00 [entrez]
AID - S0301472X02009347 [pii]
AID - 10.1016/s0301-472x(02)00934-7 [doi]
PST - ppublish
SO  - Exp Hematol. 2002 Dec;30(12):1419-27. doi: 10.1016/s0301-472x(02)00934-7.