PMID- 15968405
OWN - NLM
STAT- MEDLINE
DCOM- 20050923
LR  - 20211203
IS  - 0340-6245 (Print)
IS  - 0340-6245 (Linking)
VI  - 93
IP  - 6
DP  - 2005 Jun
TI  - Transcriptional regulation of plasminogen activator inhibitor-1 expression by 
      insulin-like growth factor-1 via MAP kinases and hypoxia-inducible factor-1 in 
      HepG2 cells.
PG  - 1176-84
AB  - Insulin-like growth factor 1 (IGF-1) and plasminogen activator inhibitor-1 
      (PAI-1) appear to play a crucial role in a number of processes associated with 
      growth and tissue remodelling. IGF-1 was shown to enhance PAI-1 expression in 
      primary hepatocytes and HepG2 hepatoma cells, but the molecular mechanisms 
      underlying this effect have not been fully elucidated. In this study, we 
      investigated the transcriptional mechanism and the signaling pathway by which 
      IGF-1 mediates induction of PAI-1 expression in HepG2 cells. By using human PAI-1 
      promoter reporter gene assays we found that mutation of the hypoxia responsive 
      element (HRE), which could bind hypoxia-inducible factor-1 (HIF-1), nearly 
      abolished the induction by IGF-1. We found that IGF-1-induced up-regulation of 
      PAI-1 expression was associated with activation of HIF-1 alpha. Furthermore,IGF-1 
      enhanced HIF-1alpha protein levels and HIF-1 DNA-binding to each HRE,E4 and E5 as 
      shown by EMSA. Mutation of the E-boxes, E4 and E5, did not affect the 
      IGF-1-dependent induction of PAI-1 promoter constructs under normoxia but 
      abolished the effect of IGF-1 under hypoxia. Inhibition of either the PI3K by 
      LY294002 or ERK1/2 by U0126 reduced HIF-1alpha protein levels while both 
      inhibitors together completely abolished the IGF-1 effect on HIF-1alpha. 
      Remarkably, transfection of HepG2 cells with vectors expressing a 
      dominant-negative PDK1 or the PKB inhibitor, TRB3, did not influence while 
      dominant-negative Raf inhibited the IGF-1 effect on HIF-1alpha. Thus, IGF-1 
      activates human PAI-1 gene expression through activation of the PI3-kinase and 
      ERK1/2 via HIF-1alpha.
FAU - Dimova, Elitsa Y
AU  - Dimova EY
AD  - Department Chemistry/Biochemistry, University of Kaiserslautern, Germany. 
      edimova@gwdg.de
FAU - Moller, Ulrike
AU  - Moller U
FAU - Herzig, Stephan
AU  - Herzig S
FAU - Fink, Trine
AU  - Fink T
FAU - Zachar, Vladimir
AU  - Zachar V
FAU - Ebbesen, Peter
AU  - Ebbesen P
FAU - Kietzmann, Thomas
AU  - Kietzmann T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
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 (Nuclear Proteins)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Transcription Factors)
RN  - 67763-96-6 (Insulin-Like Growth Factor I)
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
SB  - IM
MH  - Base Sequence
MH  - Binding Sites/genetics
MH  - Cell Line
MH  - DNA/genetics/metabolism
MH  - DNA-Binding Proteins/*metabolism
MH  - Genes, Reporter/drug effects
MH  - Hepatocytes/drug effects/metabolism
MH  - Humans
MH  - Hypoxia-Inducible Factor 1
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Insulin-Like Growth Factor I/*pharmacology
MH  - MAP Kinase Signaling System/drug effects
MH  - Neoplasms/genetics/metabolism
MH  - Nuclear Proteins/*metabolism
MH  - Phosphatidylinositol 3-Kinases/metabolism
MH  - Plasminogen Activator Inhibitor 1/*genetics
MH  - Promoter Regions, Genetic
MH  - Protein Serine-Threonine Kinases/metabolism
MH  - Proto-Oncogene Proteins/metabolism
MH  - Proto-Oncogene Proteins c-akt
MH  - RNA, Messenger/genetics/metabolism
MH  - Recombinant Proteins/pharmacology
MH  - Transcription Factors/*metabolism
MH  - Transcription, Genetic/drug effects
EDAT- 2005/06/22 09:00
MHDA- 2005/09/24 09:00
CRDT- 2005/06/22 09:00
PHST- 2005/06/22 09:00 [pubmed]
PHST- 2005/09/24 09:00 [medline]
PHST- 2005/06/22 09:00 [entrez]
AID - 05061176 [pii]
AID - 10.1160/TH04-11-0761 [doi]
PST - ppublish
SO  - Thromb Haemost. 2005 Jun;93(6):1176-84. doi: 10.1160/TH04-11-0761.