[Progress of research on tumor suppressor genes]

The multistage model of carcinogenesis during tumor progression requires that there should be consecutive genetic abnormalities of both oncogenes and tumor suppressor genes. As is true of the protein products of oncogenes, tumor suppressor proteins are found to have various cellular functions. They are involved in the regulation of adhesion, cell-cell interaction, and cytoplasmic signal transducers as well as nuclear transcription factors. The recently identified hMSH2 (human MutS homolog 2) gene in colorectal carcinomas possesses sequence homologies to DNA mismatch repair genes in bacteria and yeast. An accumulation of evidence exists to indicate the tumor suppressive functions of actin-regulatory proteins. We have shown that both mutant gelsolin His321 and human authentic gelsolin, if expressed at increased levels, may have a suppressive potential against the tumorigenicity of mouse ras-transformed cells (EJ-NIH/3T3). His321 inhibited phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis by phospholipase C gamma 1 more strongly in vitro than did wild-type gelsolin because of its higher binding capacity to phosphoinositide. We have also demonstrated that the production of gelsolin was either lost or notably reduced in human gastric carcinomas and urinary bladder cancers. The cDNAs encoding mouse or human authentic gelsolins were transfected into a urinary bladder cancer cell line. The urinary bladder transfectant lost their tumorigenicity in nude mice. All these and the facts that vinculin, alpha-actinin, erythrocyte band 4.1 family and gelsolin have both tumor-suppressive and phosphoinositides-binding activities in common suggest that these actin-regulatory proteins are a new family of effective tumor suppressors.