Research on Gene Expression Network via histone acetylation

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We have generated and analysed the mutant mice lacking transcription factor Shn-2. Shn-2 was originally identified by our group as a factor that binds to the NF-KB site, and a large protein of 270 kD with two metal-finger structures. Since Drosophila homologue of Shn acts in the dpp signaling pathway, vertebrate Shn is thought to act in the BMP/TGFβ/activin signaling pathway. Shn-2-deficient mice seems to be healthy, but have a defects of T-cell development. In the thimi of Shn-2 mutant mice, almost no single-positive T cells were observed. A series of analyses indicated that Shn-2 is essential for the positive selection of T ceils. These results suggest that the BMP/TGFβ/activin signaling pathway plays some role in the T cell development.We have also analysed the physiological role of Ski by using the Ski-deficient mice. We treated the Ski heterozygous mutant mice with chemical carcinogen DMBA. No tumors were generated in wild-type mice, whereas significant numbers of Ski heterozygotes developed the tumors such as T- and B-cell lymphomas. Further, the mouse fibroblasts prepared from the Ski-deficient embryos had increased proliferative capacity compared to wild-type cells. In addition, the introduction of activated Ki-ras into Ski-deficient mouse embryonic fibroblasts resulted in neoplastic transformation. These finding demonsrrate that Ski acts as a tumor suppressor in some types of cells.