Inhibition of cell cycle progression by the novel cyclophilin ligand sanglifehrin A is mediated through the NFkappa B-dependent activation of p53.
Sanglifehrin A belongs to a novel family of immunophilin-binding ligands. Sanglifehrin A is similar to cyclosporin A in that it binds to cyclophilins. Unlike cyclosporin A, however, the cyclophilin-sanglifehrin A complex has no effect on the calcium-dependent protein phosphatase calcineurin. It has been previously shown that sanglifehrin A specifically blocks T cell proliferation in response to interleukin 2 by inhibiting the appearance of cell cycle kinase activity cyclinE-Cdk2. How sanglifehrin A treatment leads to the cell cycle blockade has remained unknown. We report that sanglifehrin A is capable of activating the tumor suppressor gene p53 at the transcription level, leading to up-regulation of p21 that then binds and inhibits the cylcinE-Cdk2 complex. Further analysis of different elements in the p53 promoter showed that sanglifehrin A activates p53 transcription primarily through the activation of the transcription factor NFkappaB by activating IkappaB kinase in a manner that is similar to several genotoxic agents. Unlike other genotoxic drugs, sanglifehrin A does not cause DNA damage, making it a unique natural product that is capable of activating the NFkappaB signaling pathway without affecting DNA.
Zhang
L H
LH
Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Youn
H D
HD
Liu
J O
JO
D000818:Animals; D002453:Cell Cycle / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D021983:Cyclophilins / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D013141:Spiro Compounds / Q000378:metabolism / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D007783:Lactones; D008024:Ligands; D016328:NF-kappa B; D013141:Spiro Compounds; D016159:Tumor Suppressor Protein p53; C121329:sanglifehrin A; D021983:Cyclophilins