Zinc finger motif-1 antagonizes PDGF-BB-induced growth and dedifferentiation of vascular smooth muscle cells.
Zinc finger motif-1 (ZFM1) represses proinflammatory gene expression in vascular smooth muscle cells (SMCs) at a global level and thus may also be involved in the attenuation of growth factor-induced phenotype changes in these cells. Using human primary cultured thymus vein SMCs, we have investigated the molecular mechanism by which a potent SMC mitogen, platelet-derived growth factor-BB (PDGF-BB), causes a rapid decrease in ZFM1 expression in a concentration-dependent manner and consequences thereof. Reporter gene analyses and chromatin immunoprecipitation showed that PDGF-BB-induced ZFM1 repression occurs at the level of transcription through replacement of the activating transcription factor Sp1 by Egr-1. The subsequent drop in ZFM1 abundance disinhibits SMC proliferation, migration, and synthetic gene expression in a concerted manner. Stabilizing ZFM1 levels in a PDGF-BB-independent way with a GFP-ZFM1 expression construct or by using Egr-1-specific decoy oligonucleotides abrogates all PDGF-BB effects. Conversely, siRNA-mediated knockdown of ZFM1 alone not only increases the sensitivity of SMCs for PDGF-BB, but even mimics PDGF-BB-induced proliferation and gene expression. Our findings suggest that ZFM1 is an important factor for the stabilization of a contractile SMC phenotype under basal or mildly activating conditions and that, as a prerequisite for efficient action, PDGF-BB must repress ZFM1 expression to alter the SMC phenotype.
Institute of Physiology and Pathophysiology, Division of Cardiovascular Physiology, University of Heidelberg, Im Neuenheimer Feld 326, 69120 Heidelberg, Germany. cattaruzza@physiologie.uni-heidelberg.de
Marco
M
Cattaruzza
Nicole
N
Nogoy
Agnieszka
A
Wojtowicz
Markus
M
Hecker
D000595:Amino Acid Sequence; D001483:Base Sequence; D000077214:Becaplermin; D015153:Blotting, Western; D054337:Cell Dedifferentiation / Q000187:drug effects*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018613:Microscopy, Confocal; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology*; D034622:RNA Interference; D000072260:RNA Splicing Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020574:Proto-Oncogene Proteins c-sis; D000072260:RNA Splicing Factors; C107467:SF1 protein, human; D014157:Transcription Factors; D049452:Green Fluorescent Proteins; D000077214:Becaplermin