CHARACTERIZATION OF THE TGF-BETA-1-INDUCIBLE HIC-5 GENE THAT ENCODES A PUTATIVE NOVEL ZINC-FINGER PROTEIN AND ITS POSSIBLE INVOLVEMENT IN CELLULAR SENESCENCE

Transforming growth factor (TGF) beta 1 is a potent cytokine that inhi bits the growth of several types of cells. Our earlier study suggested that the mouse osteoblastic cell line, MC3T3-E1, was sensitive to gro wth inhibition by TGF beta 1 and that this effect was partly mediated by H2O2. To identify the molecules that participate in the negative re gulation of growth by these stimuli, we carried out differential scree ning of cDNA libraries and isolated a set of genes induced by TGF beta 1. Among the clones isolated, one originally named tsc-5 was found to be induced by H2O2 as well as TGF beta 1. Analysis of this cDNA renam ed hic (hydrogen peroxide-inducible clone)-5 suggested that Hic-5 prot ein has four LIM motifs, each of which contained two (or one) putative zinc fingers. The expression of hic-5 mRNA was repressed in Ki-ras-tr ansformed mouse fibroblasts and in several cell lines established from human tumor. On the other hand, its expression was augmented in the i n vitro senescent process of human diploid fibroblasts. Among the mous e organs examined, hic-5 was highly expressed in the lung and spleen. Finally, a colony formation assay using an hic-5 expression vector dri ven by the cytomegalovirus promoter suggested that hic-5 overexpressio n had a cytostatic effect on cellular growth, depending upon the cell type. Although the relationship between hic-5 function and the signal transduction pathway of TGF beta 1 remains unresolved, these results i mplied that hic-5 has some role in the growth-inhibitory pathway assoc iated with in vitro senescence, and that down-regulation of hic-5 cont ributes to tumorigenesis.