Novel role for STAT-5B in the regulation of Hsp27-FGF-2 axis facilitating thrombin-induced vascular smooth muscle cell growth and motility.
Previously, we have demonstrated that STAT-3 plays a role in thrombin-induced VSMC motility. To learn more about the role of STATs in the mitogenic and chemotactic signaling events of thrombin, here we have studied the role of STAT-5. Thrombin activated STAT-5 as measured by its tyrosine phosphorylation, DNA binding, and reporter gene activity. Inhibition of STAT-5B, but not STAT-5A, by adenovirus-mediated expression of its respective dominant-negative mutants suppressed thrombin-induced VSMC growth and motility. Thrombin induced the expression of Hsp27 and FGF-2 in a time- and STAT-5B-dependent manner in VSMC. In addition, small interfering RNA-directed depletion of Hsp27 levels or adenovirus-mediated expression of its dominant-negative mutant attenuated thrombin-induced FGF-2 expression, growth, and motility of VSMC. An increased association of STAT-5B with STAT-3 occurred in response to thrombin and adenovirus-mediated expression of dnSTAT-3 suppressed thrombin-induced Hsp27 and FGF-2 induction, DNA synthesis and motility in VSMC. Together, these results indicate that thrombin-induced VSMC growth and motility require STAT-5B/STAT-3-dependent expression of Hsp27 and FGF-2. These observations also suggest that STAT-5B/STAT-3/Hsp27/FGF-2 signaling via its involvement in the regulation of VSMC growth and motility may play an important role in the pathogenesis of vascular diseases such as restenosis after angioplasty.
Cao
Huiqing
H
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Dronadula
Nagadhara
N
Rizvi
Farhan
F
Li
Quanyi
Q
Srivastava
Kalyan
K
Gerthoffer
William T
WT
Rao
Gadiparthi N
GN
D000818:Animals; D002465:Cell Movement; D017931:DNA Primers; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000502:physiology*; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000254:growth & development / Q000502:physiology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D050796:STAT3 Transcription Factor / Q000502:physiology*; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013917:Thrombin / Q000502:physiology*; D014158:Transcription, Genetic
D017931:DNA Primers; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486114:Hspb1 protein, rat; D009363:Neoplasm Proteins; D050796:STAT3 Transcription Factor; D050799:STAT5 Transcription Factor; C494088:Stat3 protein, rat; C494097:Stat5b protein, rat; D016222:Fibroblast Growth Factor 2; D013917:Thrombin