PMID- 17384280
OWN - NLM
STAT- MEDLINE
DCOM- 20070426
LR  - 20111117
IS  - 0077-8923 (Print)
IS  - 0077-8923 (Linking)
VI  - 1090
DP  - 2006 Dec
TI  - The MAPK pathway and HIF-1 are involved in the induction of the human PAI-1 gene 
      expression by insulin in the human hepatoma cell line HepG2.
PG  - 355-67
AB  - Enhanced levels of plasminogen activator inhibitor-1 (PAI-1) are considered to be 
      a risk factor for pathological conditions associated with hypoxia or 
      hyperinsulinemia. The expression of the PAI-1 gene is increased by insulin in 
      different cells, although, the molecular mechanisms behind insulin-induced PAI-1 
      expression are not fully known yet. Here, we show that insulin upregulates human 
      PAI-1 gene expression and promoter activity in HepG2 cells and that mutation of 
      the hypoxia-responsive element (HRE)-binding hypoxia-inducible factor-1 (HIF-1) 
      abolished the insulin effects. Mutation of E-boxes E4 and E5 abolished the 
      insulin-dependent activation of the PAI-1 promoter only under normoxia, but did 
      not affect it under hypoxia. Furthermore, the insulin effect was associated with 
      activation of HIF-1alpha via mitogen-activated protein kinases (MAPKs) but not 
      PDK1 and PKB in HepG2 cells. Furthermore, mutation of a putative FoxO1 binding 
      site which was supposed to be involved in insulin-dependent PAI-1 gene expression 
      influenced the insulin-dependent activation only under normoxia. Thus, 
      insulin-dependent PAI-1 gene expression might be regulated by the action of both 
      HIF-1 and FoxO1 transcription factors.
FAU - Dimova, Elitsa Y
AU  - Dimova EY
AD  - University of Kaiserslautern, Faculty of Chemistry, Department of Biochemistry, 
      Erwin-Schroedinger Strasse 54, 67663 Kaiserslautern, Germany. edimova@gwdg.de
FAU - Kietzmann, Thomas
AU  - Kietzmann T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Ann N Y Acad Sci
JT  - Annals of the New York Academy of Sciences
JID - 7506858
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Insulin)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - Carcinoma, Hepatocellular/enzymology/*genetics/metabolism/pathology
MH  - Cell Line, Tumor
MH  - Gene Expression Regulation/*drug effects
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*physiology
MH  - Insulin/*pharmacology
MH  - Liver Neoplasms/enzymology/*genetics/metabolism/pathology
MH  - *MAP Kinase Signaling System
MH  - Plasminogen Activator Inhibitor 1/*genetics/metabolism
MH  - Promoter Regions, Genetic
MH  - RNA, Messenger/genetics
EDAT- 2007/03/27 09:00
MHDA- 2007/04/27 09:00
CRDT- 2007/03/27 09:00
PHST- 2007/03/27 09:00 [pubmed]
PHST- 2007/04/27 09:00 [medline]
PHST- 2007/03/27 09:00 [entrez]
AID - 1090/1/355 [pii]
AID - 10.1196/annals.1378.039 [doi]
PST - ppublish
SO  - Ann N Y Acad Sci. 2006 Dec;1090:355-67. doi: 10.1196/annals.1378.039.