title: Injury-induced platelet-derived growth factor receptor-alpha expression mediated by interleukin-1beta (IL-1beta) release and cooperative transactivation by NF-kappaB and ATF-4: IL-1beta facilitates HDAC-1/2 dissociation from promoter.
abstract: Platelet-derived growth factors are a family of potent mitogens and chemoattractants for fibroblasts and other cells of mesenchymal origin. Platelet-derived growth factor (PDGF) dimeric ligands (composed of A-, B-, C-, and D-chains) exert their biological activity through high affinity interactions with cell surface receptor subunits (alpha and beta). PDGF-receptor-alpha is widely implicated in the pathogenesis of hyperplastic fibrotic disease, yet the molecular mechanisms controlling its expression in response to injury are poorly understood. Here we show that PDGF-R alpha expression is induced in fibroblasts by mechanical injury and interleukin (IL)-1beta, which was abolished by neutralizing IL-1beta antibodies in the culture supernatant or inhibitors of NF-kappaB. Chromatin immunoprecipitation and electrophoretic mobility shift assays revealed the existence of a new NF-kappaB binding site at -531/-521 bp in the PDGF-R alpha promoter. We have recently shown that ATF-4 is also induced by injury (Malabanan, K. P., Kanellakis, P., Bobik, A., and Khachigian, L. M. (2008) Circ. Res. 103, 378-387), and we demonstrate here that ATF-4 binds a novel element -259/-254 and stimulates PDGF-R alpha transcription. ATF-4 and NF-kappaB interact, occupy the PDGF-R alpha promoter, and induce PDGF-R alpha transcription in a cooperative manner. IL-1beta facilitates the dissociation of histone deacetylase (HDAC)-1/2 from the PDGF-R alpha promoter, whereas the HDAC inhibitors suberoylanilide hydroxamic acid and trichostatin A potentiate IL-1beta induction of PDGF-R alpha transcription. These findings, taken together, demonstrate that injury stimulates IL-1beta secretion by fibroblasts, which activates NF-kappaB and ATF-4 and stimulates interaction with the PDGF-R alpha promoter, triggering PDGF-R alpha transcription. Physical and functional interactions between NF-kappaB and ATF-4 have not been reported in any gene. This is also the first report of HDAC regulation of PDGF-R alpha transcription.
authors: Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia.
authors: Ning
authors: N
authors: Zhang
authors: Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia. Electronic address: L.Khachigian@unsw.edu.au.
authors: Levon M
authors: LM
authors: Khachigian
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004791:Enzyme Inhibitors / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000378:metabolism; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C497109:ATF4 protein, human; D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D010982:Platelet-Derived Growth Factor; D034741:RNA, Small Interfering; C498144:Rela protein, mouse; D012097:Repressor Proteins; D051996:Transcription Factor RelA; C075278:platelet-derived growth factor A; D051701:Activating Transcription Factor 4; D020796:Receptor, Platelet-Derived Growth Factor alpha; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases; D013755:Tetradecanoylphorbol Acetate