TUMOR-SUPPRESSIVE FUNCTION OF MUTATED GELSOLIN IN RAS-TRANSFORMED CELLS

The flat revertant R1, isolated from human activated Ha-ras oncogene-t ransformed NIH3T3 fibroblasts (EJ-NIH3T3), expresses a variant form of the actin-regulatory protein gelsolin (p92-5.7). We have cloned cDNAs encoding p92-5.7 and identified as the cause of the expression of p92 -5.7 a point mutation in codon 321, which results in an amino acid cha nge from proline to histidine. In order to understand the role of p92- 5.7 in reversion of ras-transformed cells, cDNAs encoding p92-5.7 or h uman authentic gelsolin as a control were transfected into EJ-NIH3T3 c ells. All the transfectants that produced p92-5.7 and one of three tra nsfectants that produced human authentic gelsolin either lost or reduc ed tumorigenicity in syngeneic mice. These results demonstrate that mu tated gelsolin can suppress a ras tumor and suggest that authentic gel solin, if expressed at increased levels, may have a similar suppressiv e potential. Our data propose an important role for gelsolin in cellla r signal transduction pathways that involve the mammalian ras proto-on cogene.