Rapamycin inhibits poly(ADP-ribosyl)ation in intact cells |
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Authors: | Jörg Fahrer Silvia Wagner Alexander Bürkle |
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Institution: | a Molecular Toxicology Group, Department of Biology, University of Konstanz, Germany b Clinic of General, Visceral- and Transplantation Surgery, ZMF, University Hospital Tübingen, Germany |
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Abstract: | Rapamycin is an immunosuppressive drug, which inhibits the mammalian target of rapamycin (mTOR) kinase activity inducing changes in cell proliferation. Synthesis of poly(ADP-ribose) (PAR) is an immediate cellular response to genotoxic stress catalyzed mostly by poly(ADP-ribose) polymerase 1 (PARP-1), which is also controlled by signaling pathways. Therefore, we investigated whether rapamycin affects PAR production. Strikingly, rapamycin inhibited PAR synthesis in living fibroblasts in a dose-dependent manner as monitored by immunofluorescence. PARP-1 activity was then assayed in vitro, revealing that down-regulation of cellular PAR production by rapamycin was apparently not due to competitive PARP-1 inhibition. Further studies showed that rapamycin did not influence the cellular NAD pool and the activation of PARP-1 in extracts of pretreated fibroblasts. Collectively, our data suggest that inhibition of cellular PAR synthesis by rapamycin is mediated by formation of a detergent-sensitive complex in living cells, and that rapamycin may have a potential as therapeutic PARP inhibitor. |
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Keywords: | Rapamycin mTOR Poly(ADP-ribosyl)ation PARP inhibitor Fibroblasts |
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