Cyclosporin A inhibits Ca 2+ ‐mediated upregulation of the DNA repair enzyme DNA polymerase β in human peripheral blood mononuclear cells
1999; Wiley; Volume: 264; Issue: 3 Linguagem: Inglês
10.1046/j.1432-1327.1999.00700.x
ISSN1432-1033
AutoresChristoph M. Ahlers, Stefan Kreideweiß, Alfred Nordheim, Andreas Rühlmann,
Tópico(s)Biochemical and Molecular Research
ResumoAlterations in gene expression may represent an underlying cause of undesired side‐effects mediated by the immunosuppressant cyclosporin A (CsA). We employed the method of differential display PCR to identify new genes whose expression is modulated by CsA. Human peripheral blood mononuclear cells (PBMCs), or subpopulations thereof, were simultaneously stimulated with the phorbol ester 4β‐phorbol 12‐myristate 13‐acetate (PMA) and the calcium ionophore ionomycin, in the presence or absence of therapeutic concentrations of CsA. We identify the gene encoding the DNA repair enzyme DNA polymerase β (Pol β) as a novel CsA‐sensitive transcription unit. Our data show that transcription of pol β mRNA is induced by Ca 2+ and that CsA significantly inhibits PMA/ionomycin‐ and ionomycin‐mediated upregulation of both pol β mRNA and Pol β protein. The CsA‐mediated inhibition of pol β upregulation is maintained for at least 21 h after gene activation and is exerted via the phosphatase calcineurin. FK506, another immunosuppressant that targets calcineurin, also inhibits pol β upregulation, while rapamycin competes with FK506 action. This work identifies Ca 2+ as an inducer of pol β gene activity in primary blood cells. The demonstrated CsA sensitivity of this process suggests a novel molecular mechanism that may contribute to the increased tumor incidence in patients receiving CsA treatment.
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