The promotion of cell survival and regeneration in acute renal failure (ARF) is important for restitution of renal function. Epidermal growth factor (EGF) has been implicated in the regulation of cell proliferation. We provide evidence for a direct link between EGF, nuclear factor kappa B (NF-B) and cell cycle regulation (cyclin D1). EGF was found to stimulate NF-B-dependent gene transcription and DNA binding. In addition, EGF stimulated cyclin D1 promoter activity as well as cyclin D1 expression. Moreover, inhibition of NF-B caused a pronounced reduction of EGF-induced cyclin D1 promoter activity. Furthermore, both EGF-mediated NF-B activation and cyclin D1 expression was inhibited by co-expression of super IB. Taken together, these data identify NF-B and cyclin D1 as downstream targets of EGF and establish a molecular link between stimulation of EGF via activation of NF-B and cyclin D1 expression in human proximal tubular cells.