The Tg737 gene was investigated for gross alterations in a series of rodent/human liver tumors and human tumorigenic cell lines. The Tg737 gene was found to be altered in approximately 40% of the rodent chemically-induced liver tumors, 40% of the human liver tumors, and in liver, kidney and pancreatic human tumor cell lines. Ectopic re-expression of the Tg737 gene in a Tg737 deleted mouse liver tumor cell line resulted in suppression of tumorigenic growth, without altering in vitro cell culture growth. Treatment of mice which are either homozygous normal or heterozygous deleted at the Tg737 locus with the carcinogen diethylnitrosamine resulted in an increase in preneoplastic foci formation in the Tg737 heterozygous deleted mice. Ectopic expression of the Tg737 gene results in multinucleated cells, loss of Tg737 gene expression results in the proliferation of liver stem cells (oval cells) without concomitant differentation, and reexpression of the Tg737 gene reestablished responsiveness to external differentiation factors. We believe this is the first report demonstrating tumor suppression activity for a tetra-tricopeptide repeat gene family member and provides insights into the function of this family of genes in mammalian cells.