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Inhibiting the 26S Proteasome Expands Glucocorticoid Receptor Transcriptional Networks via Chromatin Modifications
Author(s) -
Kinyamu Harriet Karimi,
Yang Jun,
Archer Trevor
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.456.8
Subject(s) - proteasome , microbiology and biotechnology , biology , histone h3 , chromatin , histone , histone methyltransferase , transcription (linguistics) , transcriptional regulation , transcription factor , rna polymerase ii , gene expression , gene , biochemistry , promoter , linguistics , philosophy
Our goal is to understand the mechanisms by which the 26S proteasome regulates glucocorticoid receptor (GR)‐mediated gene transcription. The 26S proteasome, a multienzyme complex, known for its role in protein degradation, is now implicated in all stages of the transcription process. Biochemical and expression profiling experiments suggest a complex role for the 26S proteasome in GR‐mediated transcriptional regulation. Inhibiting 26S proteolytic activity results in differential expression of GR target genes, despite elevated levels of GR and RNA Pol II, indicating that GR/RNA Pol II turnover cannot explain the diververgent expression of GR targets. Chromatin modifications, such as posttranslational modifications of histones, are a dynamic way to expand transcriptional networks. In MCF‐7 breast cancer cells, transcript levels encoding several histone H3‐lysine‐methyltransferases and demethylases are changed significantly by proteasome inhibition. Furthermore, inhibiting proteasome activity leads to an increase in key histone H3‐lysine methyl marks. We stably integrated FLAG‐ tagged histone H3‐N‐terminus tail in MCF‐7 cells to query candidate effector proteins globally associated with these modifications. Mass‐Spectrometric analysis identified multiple proteins involved in mRNA processing, implicating the 26S proteasome in this process. We are currently examining the functional implications of these interactions.