4.8 Article

Hydrogen Sulfide-Linked Sulfhydration of NF-κB Mediates Its Antiapoptotic Actions

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MOLECULAR CELL
卷 45, 期 1, 页码 13-24

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CELL PRESS
DOI: 10.1016/j.molcel.2011.10.021

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资金

  1. National Institutes of Health National Research Service [1 F30 MH074191-01A2]
  2. National Institutes of Health [T32 GM007309]
  3. U.S. Public Health Service [MH18501]

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Nuclear factor kappa B (NF kappa B) is an antiapoptotic transcription factor. We show that the antiapoptotic actions of NF-kappa B are mediated by hydrogen sulfide (H(2)S) synthesized by cystathionine gamma-lyase (CSE). TNF-alpha treatment triples H(2)S generation by stimulating binding of SP1 to the CSE promoter. H(2)S generated by CSE stimulates DNA binding and gene activation of NF-kappa B, processes that are abolished in CSE-deleted mice. As CSE deletion leads to decreased glutathione levels, resultant oxidative stress may contribute to alterations in CSE mutant mice. H(2)S acts by sulfhydrating the p65 subunit of NF-kappa B at cysteine-38, which promotes its binding to the coactivator ribosomal protein S3 (RPS3). Sulfhydration of p65 predominates early after TNF-alpha treatment, then declines and is succeeded by a reciprocal enhancement of p65 nitrosylation. In CSE mutant mice, antiapoptotic influences of NF-kappa B are markedly diminished. Thus, sulfhydration of NF-kappa B appears to be a physiologic determinant of its antiapoptotic transcriptional activity.

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