Thyroid hormone induces activation of mitogen-activated protein kinase in cultured cells

Abstract

Thyroid hormone [l-thyroxine (T4)] rapidly induced phosphorylation and nuclear translocation (activation) of mitogen-activated protein kinase (MAPK) in HeLa and CV-1 cells in the absence of cytokine or growth factor. A pertussis toxin-sensitive and guanosine 5′- O-(3-thiotriphosphate)-sensitive cell surface mechanism responsive to T4and agarose-T4, suggesting a G protein-coupled receptor, was implicated. Cells depleted of MAPK or treated with MAPK pathway inhibitors showed reduced activation of MAPK and of the signal transducer and activator of transcription STAT1α by T4; they also showed reduced T4potentiation of the antiviral action of interferon-γ (IFN-γ). T4treatment caused tyrosine-phosphorylated MAPK-STAT1α nuclear complex formation and enhanced Ser-727 phosphorylation of STAT1α, in the presence or absence of IFN-γ. STAT1α-deficient cells transfected with STAT1α containing an alanine-for-serine substitution at residue 727 (STAT1αA727) showed minimal T4-stimulated STAT1α activation. IFN-γ induced the antiviral state in cells containing wild-type STAT1α (STAT1αwt) or STAT1αA727; T4potentiated IFN-γ action in STAT1αwtcells but not in STAT1αA727cells. T4-directed STAT1α Ser-727 phosphorylation is MAPK mediated and results in potentiated STAT1α activation and enhanced IFN-γ activity.