A potential role for nuclear factor of activated T-cells in receptor tyrosine kinase and G-protein-coupled receptor agonist-induced cell proliferation

• Published in: Biochemical journal 2002-11, Vol.368 (Pt 1), p.183-190
• Main Authors: Yellaturu, Chandrahasa R, Ghosh, Salil K, Rao, R K, Jennings, Lisa K, Hassid, Aviv, Rao, Gadiparthi N
• Format: Article
• Language: English
• Subjects: Animals; Cell Division - drug effects; Cell Division - physiology; DNA - biosynthesis; DNA - drug effects; DNA-Binding Proteins - physiology; Male; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; NFATC Transcription Factors; Nuclear Proteins; Platelet-Derived Growth Factor - pharmacology; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Receptors, Cell Surface - agonists; Thrombin - pharmacology; Transcription Factors - physiology
• ISSN: 0264-6021; 1470-8728
• DOI: 10.1042/BJ20020347

We have studied the role of nuclear factor of activated T-cells (NFAT) transcription factors in the induction of vascular smooth muscle cell (VSMC) growth by platelet-derived growth factor-BB (PDGF-BB) and thrombin, the receptor tyrosine kinase (RTK) and G-protein-coupled receptor (GPCR) agonists, respectively. NFATc1 but not NFATc2 or NFATc3 was translocated from the cytoplasm to the nucleus upon treatment of VSMCs with PDGF-BB or thrombin. Translocation of NFATc1 was followed by an increase in NFAT-DNA binding activity and NFAT-dependent reporter gene expression. Cyclosporin A (CsA), a potent and specific inhibitor of calcineurin, a calcium/calmodulin-dependent serine phosphatase involved in the dephosphorylation and activation of NFATs, blocked NFAT-DNA binding activity and NFAT-dependent reporter gene expression induced by PDGF-BB and thrombin. CsA also completely inhibited PDGF-BB- and thrombin-induced VSMC growth, as measured by DNA synthesis and cell number. In addition, forced expression of the NFAT-competing peptide VIVIT for calcineurin binding significantly attenuated the DNA synthesis induced by PDGF-BB and thrombin in VSMCs. Together, these findings for the first time demonstrate a role for NFATs in RTK and GPCR agonist-induced growth in VSMCs.