Premium
Protein kinase C (PKC), p38 kinase, and mitogen activated protein kinases (MAPK) signaling enhance 1 alpha, 25 dihydroxyvitamin D3 (1,25 D)‐regulated 25‐hydroxyvitamin D‐24‐hydroxylase (CYP24) gene expression in Caco‐2 cells.
Publication year - 2008
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.22.1_supplement.691.3
Subject(s) - protein kinase c , kinase , p38 mitogen activated protein kinases , c raf , protein kinase a , activator (genetics) , chemistry , biology , cancer research , microbiology and biotechnology , mitogen activated protein kinase kinase , gene , biochemistry
High vitamin D status protects against colon cancer but high CYP24 activity degrades 1,25D, reduces its genomic action, and is associated with poor colon cancer prognosis. Many kinase pathways are activated in cancer and these may affect 1,25D‐mediated CYP24 gene expression. Phorbol ester (PMA) treatment activated multiple signaling pathways and enhanced 1,25D‐induced CYP24 gene transcription (mRNA, 180%; reporter gene, 150%). Inhibition of PKC, MEK or p38 kinase each reduced PMA‐effects on 1,25D‐induced CYP24 mRNA and reporter genes by 20–40%. Reporter gene studies identified the region between −298 to +74 bp in the CYP24 promoter (containing two 1,25D response elements (VDRE)) as critical for the PMA effect. PMA enhanced 1,25D transcription through the VDRE is related to phosphorylation of the co‐activator mediator 1. Mutation of a VSE site (a putative site for PKC) and inhibiting Sp1 binding (a p38 kinase target) to DNA each reduced the PMA effect by an additional 30%. However, mutation of an EBS site (an ERK5 target site) had no impact. These data suggest that activation of kinase pathways associated with cancer (PKC, MAPK, p38 kinase) independently regulate 1,25D induced CYP24 gene expression through multiple regulatory motifs. This may reduce 1,25D‐induced anti‐cancer actions.