tacrolimus and Ataxia-Telangiectasia

The ATM kinase, when activated postnatally, exerts multiple functions to prevent the onset of ataxia-telangiectasia (AT). Using freshly isolated thymocytes from Atm-/- mice that were under stress during postnatal differentiation, we noted that thiol redox activity, as indicated by reduction of the tetrazolium MTS, and DNA turnover activity, as indicated by incorporation of [(3)H]thymidine into DNA, were both greatly increased compared with activities in thymocytes from Atm+/+ mice. This increased thymidine incorporation could be suppressed by the thiol N-acetylcysteine. In primary noncycling splenocytes, mitogens proportionally increased both the rate of [(3)H]thymidine incorporation and the rate of reduction of MTS. The mitogen-induced activities in splenocytes were not affected by ATM but were suppressed by the calcineurin-dependent inhibitor FK-506, which has no effect on these activities in thymocytes. These findings suggest that increased [(3)H]thymidine incorporation and reducing power indicate increased cell cycling in mitogenically stimulated splenocytes, whereas these two indicators represent increased FK-506-independent DNA turnover activities in thymocytes. Thus, a primary function of ATM is to activate the redox-sensitive checkpoint required for down-regulation of DNA turnover activities in developing lymphocytes. Cell-cycling checkpoints in undamaged quiescent lymphocytes are not activated by ATM with mitogenic stimulation. ATM may suppress abnormal DNA turnover and the resultant oncogenesis by regulating cellular thiol redox pathways.

Topics: Acetylcysteine; Animals; Anti-Inflammatory Agents; Ataxia Telangiectasia; Ataxia Telangiectasia Mutated Proteins; Cell Cycle; Cell Cycle Proteins; Cells, Cultured; Dexamethasone; DNA; DNA-Binding Proteins; Female; Flow Cytometry; Free Radical Scavengers; Humans; Immunosuppressive Agents; Lymphocytes; Male; Mice; Mitogens; Oxidation-Reduction; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Spleen; Tacrolimus; Thymidine; Thymus Gland; Tumor Suppressor Proteins