The imprinted gene Peg3 encodes a zinc-finger protein which has been proposed to be involved in tumor necrosis factor alpha (TNF) signaling via an interaction with TNF receptor-associated factor 2 (TRAF2). Primary embryonic fibroblasts derived from mice with a null mutation in Peg3 showed no abnormalities in TNF-induced nuclear translocation of nuclear factor kappaB (NF-kappaB) or phosphorylation of the mitogen-activated protein kinases, extracellular signal-regulated kinases 1 and 2, c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38. In addition, the loss of Peg3 function did not increase the sensitivity of the cells to the cytotoxic action of TNF. These results suggest that Peg3 does not play an essential role in TNF signal transduction.