PMID- 20216986
OWN - NLM
STAT- MEDLINE
DCOM- 20101005
LR  - 20101007
IS  - 2567-689X (Electronic)
IS  - 0340-6245 (Linking)
VI  - 103
IP  - 5
DP  - 2010 May
TI  - The adaptor protein Ruk/CIN85 activates plasminogen activator inhibitor-1 (PAI-1) 
      expression via hypoxia-inducible factor-1alpha.
PG  - 901-9
LID - 10.1160/TH09-08-0524 [doi]
AB  - Increased levels of plasminogen activator inhibitor-1 (PAI-1) indicate an 
      enhanced risk of ischaemic/hypoxic cardiovascular events and a poor prognosis. 
      The expression of PAI-1 can be induced by various stimuli including hypoxia, 
      insulin and insulin-like growth factor 1 (IGF-1). The hypoxia-inducible factor-1 
      (HIF-1) is critical for hypoxia or insulin/IGF-1 mediated PAI-1 induction, but 
      the components involved in merging the signals are not known so far. The 
      adaptor/scaffold protein Ruk/CIN85 may be a candidate since it plays important 
      roles in the regulation of processes associated with cardiovascular and 
      oncological diseases such as downregulation of receptor tyrosine kinases, 
      apoptosis, adhesion and invasion. Therefore, it was the aim of this study to 
      investigate the involvement of Ruk/CIN85 in the regulation of PAI-1 expression. 
      It was found that Ruk/CIN85 induced PAI-1 mRNA and protein expression both under 
      normoxia and hypoxia. The induction of PAI-1 expression by Ruk/CIN85 occurred at 
      the transcriptional level since the half-life of PAI-1 mRNA was not affected in 
      cells overexpressing Ruk/CIN85 and reporter gene assays using wild-type and 
      mutant human PAI-1 promoter luciferase constructs showed that the hypoxia 
      responsive element was responsible for Ruk/CIN85 effects. Further, knocking down 
      HIF-1alpha abolished not only the hypoxia-dependent but also the 
      Ruk/CIN85-dependent PAI-1 induction. In addition, transient or stable 
      overexpression of Ruk/CIN85 also induced HIF-1alpha protein levels and HIF-1 
      activity and knocking down Ruk/CIN85 reversed these effects. Thereby, Ruk/CIN85 
      interfered with the proline hydroxylation-dependent HIF-1alpha protein 
      destabilisation. Together, these results provide the first evidence that 
      Ruk/CIN85 induces PAI-1 expression via modulation of HIF-1alpha stability.
FAU - Samoylenko, Anatoly
AU  - Samoylenko A
AD  - Laboratory of Cell Signalling, Palladin Institute of Biochemistry, National 
      Academy of Sciences of Ukraine, Kiev, Ukraine.
FAU - Dimova, Elitsa Y
AU  - Dimova EY
FAU - Kozlova, Nina
AU  - Kozlova N
FAU - Drobot, Lyudmyla
AU  - Drobot L
FAU - Kietzmann, Thomas
AU  - Kietzmann T
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100309
PL  - Germany
TA  - Thromb Haemost
JT  - Thrombosis and haemostasis
JID - 7608063
RN  - 0 (Adaptor Proteins, Signal Transducing)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SH3KBP1 protein, human)
SB  - IM
MH  - Adaptor Proteins, Signal Transducing/genetics/*metabolism
MH  - Blotting, Western
MH  - Cell Hypoxia
MH  - Cell Line, Tumor
MH  - Cloning, Molecular
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism
MH  - Plasminogen Activator Inhibitor 1/*biosynthesis/genetics
MH  - RNA, Small Interfering/genetics
MH  - Signal Transduction/genetics
MH  - Transcriptional Activation/genetics
MH  - Transgenes/genetics
EDAT- 2010/03/11 06:00
MHDA- 2010/10/06 06:00
CRDT- 2010/03/11 06:00
PHST- 2009/08/03 00:00 [received]
PHST- 2009/12/15 00:00 [accepted]
PHST- 2010/03/11 06:00 [entrez]
PHST- 2010/03/11 06:00 [pubmed]
PHST- 2010/10/06 06:00 [medline]
AID - 09-08-0524 [pii]
AID - 10.1160/TH09-08-0524 [doi]
PST - ppublish
SO  - Thromb Haemost. 2010 May;103(5):901-9. doi: 10.1160/TH09-08-0524. Epub 2010 Mar 
      9.