Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling

Citation
C. Bousquet et S. Melmed, Critical role for STAT3 in murine pituitary adrenocorticotropin hormone leukemia inhibitory factor signaling, J BIOL CHEM, 274(16), 1999, pp. 10723-10730
Citations number
45
Categorie Soggetti
Biochemistry & Biophysics
Journal title
JOURNAL OF BIOLOGICAL CHEMISTRY
ISSN journal
00219258 → ACNP
Volume
274
Issue
16
Year of publication
1999
Pages
10723 - 10730
Database
ISI
SICI code
0021-9258(19990416)274:16<10723:CRFSIM>2.0.ZU;2-S
Abstract
Leukemia inhibitory factor (LIF) is a pleiotropic neuroimmune cytokine that promotes corticotroph cell differentiation and induces proopiomelanocortin (POMC) mRNA expression and adrenocorticotropin hormone (ACTH) secretion. H owever, molecular mechanisms for this induction remain elusive. We therefor e developed ACTH-secreting AtT20 transformants for wild-type or mutated STA T3, a cytokine signaling molecule, to address whether STAT3 is a determinan t of LIF-mediated ACTH regulation. We show that these mutants act in a domi nant negative manner by blocking endogenous STAT3 tyrosine phosphorylation or STAT3 DNA binding. Attenuation of STAT3 activity in the dominant negativ e AtT20 clones prevented LIF from promoting transcriptional activation of t he POMC promoter (2.1-fold), whereas this LIF action was enhanced (7.7-fold ; p < 0.05) in wild-type STAT3-overexpressing clones in comparison to mock- transfected cells (4.5-fold). However, wildtype or dominant negative STAT3- overexpressing clones showed comparable (4-fold) POMC induction after treat ment with cyclic adenosine monophosphate (cAMP), an alternate inducer of PO MC transcription, indicating the STAT3 specificity for LIF signaling. Moreo ver, dominant negative inactivation of STAT3 activity resulted in abrogatio n of LIF-induced POMC mRNA levels and ACTH secretion, confirming the in viv o role of STAT3 in LIF-mediated corticotroph action. Chemical or molecular blockade of the mitogen-activated protein kinase pathway did not affect LIF -mediated corticotroph function. These results indicate that STAT3 is a cri tical intrapituitary component of the LIF-mediated neuroimmunoendocrine int erface in corticotroph cells.