THE TETRATRICOPEPTIDE REPEAT CONTAINING TG737 GENE IS A LIVER NEOPLASIA TUMOR-SUPPRESSOR GENE

The Tg737 gene was investigated for gross alterations in a series of r odent/human liver tumors and human tumorigenic cell lines. The Tg737 g ene was found to be altered in approximately 40% of the rodent chemica lly-induced liver tumors, 40% of the human liver tumors, and in liver, kidney and pancreatic human tumor cell lines. Ectopic re-expression o f the Tg737 gene in a Tg737 deleted mouse liver tumor cell line result ed in suppression of tumorigenic growth, without altering in vitro cel l culture growth. Treatment of mice which are either homozygous normal or heterozygous deleted at the Tg737 locus with the carcinogen diethy lnitrosamine resulted in an increase in preneoplastic foci formation i n the Tg737 heterozygous deleted mice. Ectopic expression of the Tg737 gene results in multinucleated cells, loss of Tg737 gene expression r esults in the proliferation of liver stem cells (oval cells) without c oncomitant differentiation, and reexpression of the Tg737 gene reestab lished responsiveness to external differentiation factors. We believe this is the first report demonstrating tumor suppression activity for a tetratricopeptide repeat gene family member and provides insights in to the function of this family of genes in mammalian cells.