The functions of DNA topoisomerase and genes regulated by DNA topology in differentiation.

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In cellular differentiation, various gene expression is regulated by altering DNA topology which is tightly modulated by DNA topoisomerase I and II.We identified two genes that were suppressed early in the incubation with topoisomerase inhibitors. One was highly homologous to hnRNPA1 which modulates splicing of selected transcripts or stabilizes mRNAs. The other was a novel gene, named as TIS, which spanned about 21 kb including 11 exons and was present as a single copy. It was expressed in most mouse tissues, but its function was unknown. Then, we analyzed the roles of topoisomerases and TIS gene in human salivary gland tumor cells (HSG) treated by differentiating agents such as topoisomerase inhibitor (etoposide), trans-retinoic acid (tRA) or dibutyryl cyclic AMP (bt2cAMP). Expression of topoisomerase I was reduced at the early state by tRA treatment but not by bt2cAMP.Expression of topoisomerase I was decreased by tRA, but at a lesser extent by bt2cAMP.The level of topoisomerase IIβ … More was low and was not altered. The results suggest that downregulation of topoisomerase IIα involves in arrest of cellular proliferation and initiation of differentiation through alterations in DNA topology. TIS gene expression was reduced at the early stage after the treatment of the agents, suggesting the involvement of TIS gene in differentiation. Recently, TIS has been known to play certain important role in neoplastic transformation, cytokine-induced T cell activation, neoplastic proliferation, and apoptosis.Apoptosis is induced as terminal differentiation in various cells inculuding salivary gland acinar cells. Salivary gland acinar cells and HSG cells underwent apoptosis by a topoisomerase II inhibitor, etoposide. PKCδ is known to be cleaved by caspase-3 in apoptotic cells. We found a novel isoform of PKCδ which was insensitive to caspase-3 in mouse salivary glands. These findings suggest that a novel PKCδ isoform may have some important role in terminal differentiation of salivary gland cells.Further studies are required to elucidate the role of topoisomerases and TIS gene using homogeneously differentiating cells as a model. Less