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PKC phosphorylation of Med25 is critical for Mediator assembly: Implications for HNF4α signaling in drug metabolism
Author(s) -
Zhang ShuYun,
Surapureddi Sailesh,
Goldstein Joyce A.
Publication year - 2013
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.27.1_supplement.1180.1
Subject(s) - mediator , phosphorylation , rna polymerase ii , microbiology and biotechnology , phosphorylation cascade , transcription factor , dephosphorylation , biology , chemistry , protein phosphorylation , biochemistry , promoter , gene expression , protein kinase a , gene , phosphatase
HNF 4α, a member of the nuclear receptor superfamily regulates a variety of critical metabolic pathways with the help of conserved multisubunit Mediator complex that acts as a functional interface between regulatory transcription factors and the general RNA polymerase II initiation apparatus. Med25, a variable partner of Mediator complex has been found to enhance RNA polymerase II recruitment significantly and stabilize transcription complexes at the promoter of drug metabolism genes. Our lab has previously shown that Med25 plays a pivotal role in modulating HNF4α; transcription activity, there by regulating drug metabolism in primary human hepatocytes. Here, we report that Med25 is phosphorylated by PKC subunits as determined by in vitro phosphorylation assays, inhibition of PKC subunits, and mutation of the phosphorylation sites. We postulate that the phosphorylation status of Med25 is critical for dephosphorylation of HNF4α; and phosphorylation of RNA Pol –II (CTD). Our findings suggest that Med25 phosphorylation by PKC is a novel regulatory mechanism that promotes association with Mediator complex and, as such, may facilitate a feed‐forward action of HNF4α; signaling in drug metabolism.