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 inhibits the growth of several types of cells. Our earlier study suggested that the mouse osteoblastic cell line, MC3T3-E1, was sensitive to growth inhibition by TGF beta 1 and that this effect was partly mediated by H2O2. To identify the molecules that participate in the negative regulation of growth by these stimuli, we carried out differential screening 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 renamed hic (hydrogen peroxide-inducible clone)-5 suggested that Hic-5 protein 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-transformed mouse fibroblasts and in several cell lines established from human tumor. On the other hand, its expression was augmented in the in vitro senescent process of human diploid fibroblasts. Among the mouse organs examined, hic-5 was highly expressed in the lung and spleen. Finally, a colony formation assay using an hic-5 expression vector driven by the cytomegalovirus promoter suggested that hic-5 overexpression 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 implied that hic-5 has some role in the growth-inhibitory pathway associated with in vitro senescence, and that down-regulation of hic-5 contributes to tumorigenesis.
Shibanuma
M
M
Department of Microbiology, Showa University School of Pharmaceutical Sciences, Tokyo, Japan.
Mashimo
J
J
Kuroki
T
T
Nose
K
K
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016922:Cellular Senescence; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005347:Fibroblasts; D005786:Gene Expression Regulation; D011905:Genes, ras / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D051379:Mice; D008969:Molecular Sequence Data; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D014176:Protein Biosynthesis; D012641:Selection, Genetic; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016335:Zinc Fingers
D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; C490351:TGFB1I1 protein, human; C090090:Tgfb1i1 protein, mouse; D016212:Transforming Growth Factor beta; D006861:Hydrogen Peroxide