NF-kappaB subtypes regulate CCCTC binding factor affecting corneal epithelial cell fate.
CCCTC binding factor (CTCF) controls DNA imprinting, insulates important gene expression, and mediates growth factor- and stress-induced cell fate. However, regulatory mechanisms involved in intracellular CTCF activity are largely unknown. In this study, we show that epidermal growth factor (EGF)-induced increase and UV stress-induced decrease in CTCF activities mediate human corneal epithelial cell proliferation and apoptosis, respectively. CTCF is regulated by activation of different NF-kappaB subtypes via stimulation by EGF and UV stress. EGF-induced formation of a p65/p50 heterodimer activated CTCF transcription to promote cellular proliferation. This was accomplished by the heterodimer binding to a kappaB site in the promoter region of CTCF gene. In contrast, UV stress induced formation of a p50/p50 homodimer, which suppressed CTCF expression leading to apoptosis. Thus, CTCF by itself plays a central role in mediating the dichotomous effects of growth factor- and stress-stimulated NF-kappaB activation on cell survival and death. These results suggest that CTCF is a downstream component of the NF-kappaB pathway involved in the core transcriptional network of cell fate.
Lu
Luo
L
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502. Electronic address: lluou@ucla.edu.
Wang
Ling
L
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502.
Li
Tie
T
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502.
Wang
Jie
J
Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Torrance, California 90502.
D021581:Active Transport, Cell Nucleus; D000076246:CCCTC-Binding Factor; D016923:Cell Death; D019070:Cell Lineage; D049109:Cell Proliferation; D002470:Cell Survival; D019281:Dimerization; D004815:Epidermal Growth Factor / Q000737:chemistry; D004847:Epithelial Cells / Q000166:cytology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000737:chemistry*; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
D000076246:CCCTC-Binding Factor; C000619697:CTCF protein, human; D016328:NF-kappa B; D012097:Repressor Proteins; D004815:Epidermal Growth Factor