Inhibition of Cell Cycle Progression by the Novel Cyclophilin Ligand Sanglifehrin A Is Mediated through the NFκB-dependent Activation of p53

Ling Hua Zhang, Hong Duk Youn, Jun O. Liu

Research output: Contribution to journalArticle

Abstract

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 NFκB by activating IκB 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 NFκB signaling pathway without affecting DNA.

Original languageEnglish (US)
Pages (from-to)43534-43540
Number of pages7
JournalJournal of Biological Chemistry
Volume276
Issue number47
DOIs
StatePublished - Nov 23 2001
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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