Ligand-dependent corepressor contributes to transcriptional repression by C2H2 zinc-finger transcription factor ZBRK1 through association with KRAB-associated protein-1.
We identified a novel interaction between ligand-dependent corepressor (LCoR) and the corepressor KRAB-associated protein-1 (KAP-1). The two form a complex with C2H2 zinc-finger transcription factor ZBRK1 on an intronic binding site in the growth arrest and DNA-damage-inducible α (GADD45A) gene and a novel site in the fibroblast growth factor 2 (FGF2) gene. Chromatin at both sites is enriched for histone methyltransferase SETDB1 and histone 3 lysine 9 trimethylation, a repressive epigenetic mark. Depletion of ZBRK1, KAP-1 or LCoR led to elevated GADD45A and FGF2 expression in malignant and non-malignant breast epithelial cells, and caused apoptotic death. Loss of viability could be rescued by simultaneous knockdowns of FGF2 and transcriptional coregulators or by blocking FGF2 function. FGF2 was not concurrently expressed with any of the transcriptional coregulators in breast malignancies, suggesting an inverse correlation between their expression patterns. We propose that ZBRK1, KAP-1 and LCoR form a transcriptional complex that silences gene expression, in particular FGF2, which maintains breast cell viability. Given the broad expression patterns of both LCoR and KAP-1 during development and in the adult, this complex may have several regulatory functions that extend beyond cell survival, mediated by interactions with ZBRK1 or other C2H2 zinc-finger proteins.
Department of Physiology, McGill University, Montreal, QC, Canada.
Mario R
MR
Calderon
Department of Physiology, McGill University, Montreal, QC, Canada.
Mark
M
Verway
Department of Biochemistry, Université de Montréal, Montreal, QC, Canada Institut de Recherche en Immunologie et Cancérologie (IRIC), Université de Montréal, Montreal, QC, Canada.
Radia Ouelaa
RO
Benslama
Institut de Recherche en Immunologie et Cancérologie (IRIC), Université de Montréal, Montreal, QC, Canada.
Mirela
M
Birlea
Department of Physiology, McGill University, Montreal, QC, Canada.
Manuella
M
Bouttier
Department of Physiology, McGill University, Montreal, QC, Canada.
Vassil
V
Dimitrov
Department of Biochemistry, Université de Montréal, Montreal, QC, Canada Institut de Recherche en Immunologie et Cancérologie (IRIC), Université de Montréal, Montreal, QC, Canada.
Sylvie
S
Mader
Department of Physiology, McGill University, Montreal, QC, Canada Department of Medicine, McGill University, Montreal, QC, Canada john.white@mcgill.ca.
John H
JH
White
D017209:Apoptosis; D001665:Binding Sites; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007438:Introns; D061986:MCF-7 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D016222:Fibroblast Growth Factor 2; D009687:Nuclear Proteins; D012097:Repressor Proteins; D000076183:Tripartite Motif-Containing Protein 28; C439070:GADD45A protein, human; D000097642:GADD45 Proteins; C472166:LCOR protein, human; C422407:ZNF350 protein, human; C101116:TRIM28 protein, human