ESE-1 is a potent repressor of type II collagen gene (COL2A1) transcription in human chondrocytes.
The epithelium-specific ETS (ESE)-1 transcription factor is induced in chondrocytes by interleukin-1beta (IL-1beta). We reported previously that early activation of EGR-1 by IL-1beta results in suppression of the proximal COL2A1 promoter activity by displacement of Sp1 from GC boxes. Here we report that ESE-1 is a potent transcriptional suppressor of COL2A1 promoter activity in chondrocytes and accounts for the sustained, NF-kappaB-dependent inhibition by IL-1beta. Of the ETS factors tested, this response was specific to ESE-1, since ESE-3, which was also induced by IL-1beta, suppressed COL2A1 promoter activity only weakly. In contrast, overexpression of ETS-1 increased COL2A1 promoter activity and blocked the inhibition by IL-1beta. These responses to ESE-1 and ETS-1 were confirmed using siRNA-ESE1 and siRNA-ETS1. In transient cotransfections, the inhibitory responses to ESE-1 and IL-1beta colocalized in the -577/-132 bp promoter region, ESE-1 bound specifically to tandem ETS sites at -403/-381 bp, and IL-1-induced binding of ESE-1 to the COL2A1 promoter was confirmed in vivo by ChIP. Our results indicate that ESE-1 serves a potent repressor function by interacting with at least two sites in the COL2A1 promoter. However, the endogenous response may depend upon the balance of other ETS factors such as ETS-1, and other IL-1-induced factors, including EGR-1 at any given time. Intracellular ESE-1 staining in chondrocytes in cartilage from patients with osteoarthritis (OA), but not in normal cartilage, further suggests a fundamental role for ESE-1 in cartilage degeneration and suppression of repair.
Peng
Haibing
H
Department of Medicine, Beth Israel Deaconess Medical Center, New England Baptist Bone and Joint Institute, Boston, Massachusetts, USA.
Tan
Lujian
L
Osaki
Makoto
M
Zhan
Yumei
Y
Ijiri
Kosei
K
Tsuchimochi
Kaneyuki
K
Otero
Miguel
M
Wang
Hong
H
Choy
Bob K
BK
Grall
Franck T
FT
Gu
Xuesong
X
Libermann
Towia A
TA
Oettgen
Peter
P
Goldring
Mary B
MB
D002356:Cartilage / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D053583:Interleukin-1beta / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection; D015854:Up-Regulation
C499177:COL2A1 protein, human; D002843:Chromatin; D024043:Collagen Type II; D004268:DNA-Binding Proteins; C403306:EHF protein, human; C105529:ELF3 protein, human; C494041:ETS1 protein, human; D053583:Interleukin-1beta; D016328:NF-kappa B; D050784:Proto-Oncogene Protein c-ets-1; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors