The nuclear factor-kappaB (NF-kappaB) pathway is involved in a variety of cellular functions, including cell proliferation, differentiation, development, oncogenesis, and apoptosis. In this study, we report on cloning and characterization of the human TSR2 (also known as 20S rRNA accumulation homolog), a protein containing a WGG motif, which has no known specific function, although this protein is conserved during evolution across different species. The cDNA sequence contains a 576 bp open reading frame, encoding a 191 amino acid protein with a predicted molecular mass of 20.9 kDa. Northern blot analysis revealed broad TSR2 mRNA expression in human tissues. Overexpression of TSR2 in human epidermal HEp-2 cells inhibited the transcriptional activity of NF-kappaB, with or without tumor necrosis factor a stimulus, and induced HEp-2 cell apoptosis. This data for the first time suggests that TSR2 is involved in the NF-kappaB signaling pathway and may regulate apoptosis.