The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of stat proteins
S. Uddin et al., The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of stat proteins, J BIOL CHEM, 275(36), 2000, pp. 27634-27640
The p38 mitogen-activated protein (MAP) kinase is activated during engageme
nt of the type I interferon (TFN) receptor and mediates signals essential f
or IFN alpha-dependent transcriptional activation via interferon-stimulated
response elements without affecting formation of the ISGF3 complex. In the
present study, we provide evidence that the small GTPase Rad is activated
in a type I IFN-dependent manner and that its function is required for down
stream engagement of the p38 MAP kinase pathway. We also demonstrate that p
38 is required for IFN alpha-dependent gene transcription via GAS elements
and regulates activation of the promoter of the PML gene that mediates grow
th inhibitory responses. In studies to determine whether the regulatory eff
ects of p38 are mediated by serine phosphorylation of Stat1 or Stat3, we fo
und that the p38 kinase inhibitors SB203580 or SB202190 or overexpression o
f a dominant negative p38 mutant do not inhibit phosphorylation of Stat1 or
Stat3 on Ser-727 in several IFN alpha-sensitive cell lines. Altogether the
se data demonstrate that the Rac1/p38 MAP kinase signaling cascade plays a
critical role in type I IFN signaling, functioning in cooperation with the
Stat-pathway, to regulate transcriptional regulation of IFN alpha-sensitive
genes and generation of growth inhibitory responses.