PMID- 19168719
OWN - NLM
STAT- MEDLINE
DCOM- 20090610
LR  - 20220317
IS  - 0363-6135 (Print)
IS  - 1522-1539 (Electronic)
IS  - 0363-6135 (Linking)
VI  - 296
IP  - 4
DP  - 2009 Apr
TI  - Sp1-dependent activation of KLF4 is required for PDGF-BB-induced phenotypic 
      modulation of smooth muscle.
PG  - H1027-37
LID - 10.1152/ajpheart.01230.2008 [doi]
AB  - There is clear evidence that the phenotypic modulation of smooth muscle cells 
      (SMCs) contributes to the pathophysiology of vascular disease. Phenotypic 
      modulation refers to the unique ability of SMCs to alter their phenotype in 
      response to extracellular stimuli and is hallmarked by the loss of SMC marker 
      gene expression. The transcription factor Kruppel-like factor 4 (KLF4) is a known 
      powerful negative regulator of SMC marker gene expression that works, in part, by 
      decreasing the expression of the serum response factor (SRF) myocardin. KLF4 is 
      not expressed in healthy adult SMCs but is increased in SMCs in response to 
      vascular injury in vivo or PDGF-BB treatment in vitro. The aim of the present 
      study was to determine the molecular mechanisms that regulate the expression of 
      KLF4 in phenotypically modulated SMCs. The results demonstrated that the 
      transcription factor stimulating protein-1 (Sp1) regulated the expression of KLF4 
      in SMCs. The KLF4 promoter contains three consensus Sp1 binding sites. Using a 
      series of truncated KLF4 promoters, we showed that only fragments containing 
      these Sp1 sites could be activated by PDGF-BB. In addition, overexpression of Sp1 
      alone was sufficient to increase the activity of the KLF4 promoter. Moreover, 
      inhibiting Sp1 expression with small-interfering RNA attenuated the effects of 
      PDGF-BB on KLF4 expression. Mutation of the three Sp1 sites within the KLF4 
      promoter abolished both baseline and PDGF-BB-induced activity. Finally, the 
      results demonstrated enhanced Sp1 binding to the KLF4 promoter in SMCs treated 
      with PDGF-BB in vitro and following vascular injury in vivo. Taken together, the 
      results suggest a novel role for Sp1 in increasing the expression of KLF4 in 
      phenotypically modulated SMCs.
FAU - Deaton, Rebecca A
AU  - Deaton RA
AD  - Department of Molecular Physiology and Biophysics, Cardiovascular Research 
      Center, University of Virginia, Charlottesville, VA, USA.
FAU - Gan, Qiong
AU  - Gan Q
FAU - Owens, Gary K
AU  - Owens GK
LA  - eng
GR  - P01-HL-19242/HL/NHLBI NIH HHS/United States
GR  - R01-HL-38854/HL/NHLBI NIH HHS/United States
GR  - R37-HL-57353/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20090123
PL  - United States
TA  - Am J Physiol Heart Circ Physiol
JT  - American journal of physiology. Heart and circulatory physiology
JID - 100901228
RN  - 0 (Angiogenesis Inducing Agents)
RN  - 0 (Klf4 protein, rat)
RN  - 0 (Kruppel-Like Factor 4)
RN  - 0 (Kruppel-Like Transcription Factors)
RN  - 0 (Platelet-Derived Growth Factor)
RN  - 0 (Proto-Oncogene Proteins c-sis)
RN  - 0 (RNA, Small Interfering)
RN  - 0 (Sp1 Transcription Factor)
RN  - 1B56C968OA (Becaplermin)
SB  - IM
MH  - Angiogenesis Inducing Agents/*pharmacology
MH  - Animals
MH  - Base Sequence
MH  - Becaplermin
MH  - Cells, Cultured
MH  - Disease Models, Animal
MH  - Kruppel-Like Factor 4
MH  - Kruppel-Like Transcription Factors/*metabolism
MH  - Male
MH  - Molecular Sequence Data
MH  - Muscle, Smooth, Vascular/cytology/*drug effects/*metabolism
MH  - Phenotype
MH  - Platelet-Derived Growth Factor/*pharmacology
MH  - Protein Binding/physiology
MH  - Proto-Oncogene Proteins c-sis
MH  - RNA, Small Interfering/pharmacology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Sp1 Transcription Factor/genetics/*metabolism
MH  - Transfection
MH  - Up-Regulation/physiology
MH  - Vascular Diseases/metabolism
PMC - PMC2670704
EDAT- 2009/01/27 09:00
MHDA- 2009/06/11 09:00
PMCR- 2010/04/01
CRDT- 2009/01/27 09:00
PHST- 2009/01/27 09:00 [entrez]
PHST- 2009/01/27 09:00 [pubmed]
PHST- 2009/06/11 09:00 [medline]
PHST- 2010/04/01 00:00 [pmc-release]
AID - 01230.2008 [pii]
AID - H-01230-2008 [pii]
AID - 10.1152/ajpheart.01230.2008 [doi]
PST - ppublish
SO  - Am J Physiol Heart Circ Physiol. 2009 Apr;296(4):H1027-37. doi: 
      10.1152/ajpheart.01230.2008. Epub 2009 Jan 23.