Elevated Egr-1 in human atherosclerotic cells transcriptionally represses the transforming growth factor-beta type II receptor.
Atherosclerotic lesions may progress due to a "failure to die" by vascular repair cells. Egr-1, a zinc finger transcription factor, is elevated more than 5-fold in human carotid lesions relative to the adjacent tunica media. Lesion cells in vitro also express 2-3-fold higher Egr-1 mRNA and protein levels but express much lower levels of the transforming growth factor-beta (TGF-beta) Type II receptor (TbetaR-2) and are functionally resistant to the antiproliferative effects of TGF-beta. Lesion cells fail to express a TbetaR-2 promoter/chloramphenicol acetyltransferase (CAT) construct but overexpress an Egr-1-inducible platelet-derived growth factor-A promoter/CAT construct. Transfection of Egr-1 cDNA represses TbetaR-2/CAT constructs but induces PDGF-A/CAT. Egr-1 transfection reduces the levels of TbetaR-2 and confers resistance to the antiproliferative effect of TGF-beta1. Egr-1 can interact directly with both the -143 Sp1 site and the positive regulatory element 2 (PRE2) (ERT/ets) region of the TbetaR-2 promoter. Thus, although activating a family of stress-responsive genes, Egr-1 also transcriptionally represses one of the major inhibitory pathways that restrains vascular repair.
Du
B
B
Department of Medicine, Division of Hematology/Oncology, Weill Medical College of Cornell University New York, New York 10021, USA.
Fu
C
C
Kent
K C
KC
Bush
H
H
Schulick
A H
AH
Kreiger
K
K
Collins
T
T
McCaffrey
T A
TA
D001158:Arteries / Q000378:metabolism; D001161:Arteriosclerosis / Q000378:metabolism*; D001665:Binding Sites; D015153:Blotting, Western; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D003001:Cloning, Molecular; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003720:Densitometry; D004305:Dose-Response Relationship, Drug; D051766:Early Growth Response Protein 1; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D017930:Genes, Reporter; D006801:Humans; D017874:Immediate-Early Proteins; D020932:Nerve Growth Factor / Q000378:metabolism; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D012313:RNA / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis*; D014158:Transcription, Genetic; D014162:Transfection; D014680:Veins / Q000378:metabolism; D016335:Zinc Fingers
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017874:Immediate-Early Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D014157:Transcription Factors; C075278:platelet-derived growth factor A; D016222:Fibroblast Growth Factor 2; D012313:RNA; D020932:Nerve Growth Factor; D015500:Chloramphenicol O-Acetyltransferase; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II