The Rac1/p38 mitogen-activated protein kinase pathway is required for interferon alpha-dependent transcriptional activation but not serine phosphorylation of stat proteins

Citation
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
Citations number
57
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
275
Issue
36
Year of publication
2000
Pages
27634 - 27640
Database
ISI
SICI code
0021-9258(20000908)275:36<27634:TRMPKP>2.0.ZU;2-A
Abstract
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.