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.