Suppression of anchorage-independent growth of human cancer cell lines by the drs gene

We have previously reported that the drs gene, whose mRNA expression is downregulated by retroviral oncogenes such as v-src and v-K-ras, has the ability to suppress transformation by v-src in a rat cell line F2408. We have now isolated a human homolog of this gene (h-drs) and found that the expression of h-drs mRNA is markedly downregulated in a variety of human cancer cell lines including those of the colon, bladder, and ovary. To investigate the function of the drs gene as a tumor suppressor in human cancer cells, we constructed recombinant amphotropic retrovirus containing the drs gene, introduced this virus into human cancer cell lines whose drs expression was downregulated and found that drs has the ability to suppress anchorage-independent growth of these cells without disturbing cell proliferation. Analyses with deletion mutants of the drs gene revealed that both the C-terminal region inside the transmembrane domain and three consensus repeats in the N-terminal region are essential for the suppression of anchorage-independent growth of the cells. We also found that the G1-S progression of the cell cycle and expression of cyclin A mRNA were significantly suppressed in T24 cells expressing the drs gene under non-adhesion culture conditions. In contrast, the expression of cyclin D and E and the phosphorylation of Rb protein were not affected by ectopic expression of the drs gene, suggesting that an Rb-independent downregulation of cyclin A is involved in the suppression of anchorage-independent growth by means of the drs gene.