Effect of decreased fte-1 gene expression on protein synthesis, cell growth, and transformation.

The fte-1 gene, previously cloned in our laboratory as a putative v-fos transformation effector gene (C.J. Kho and H. Zarbl, Proc. Natl. Acad. Sci. USA, 89: 2200-2204, 1992), has been shown to encode ribosomal protein S3a. Comparison of fte-1 expression in a variety of normal and transformed cells indicated that elevated expression of fte-1 mRNA was frequently associated with transformation of rodent and human cells. In an effort to understand how monoallelic disruption of fte-1 is able to block v-fos-induced cell transformation, we examined the pattern of fte-1 expression during cell cycle progression and determined its effects on protein synthesis and cell growth. In synchronously cultured human fibroblasts, fte-1 mRNA was found to accumulate in cells undergoing DNA synthesis, suggesting that its expression is correlated with S-phase progression. fte-1 does not function as a dominant oncogene because ectopic overexpression of fte-1 in normal Rat-1 fibroblasts failed to induce cell transformation. However, the expression of antisense fte-1 resulted in growth inhibition. Monoallelic disruption of the fte-1 gene in v-fos-transformed Rat-1 fibroblasts resulted not only in loss of the transformed phenotype but also in a decreased rate of protein synthesis due to decreased polysome formation. Taken together, these results indicate that the accumulation of ribosomal subunits and the rate of protein synthesis are important modulators of neoplastic transformation and cell growth.