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J Biol Chem, Vol. 274, Issue 16, 10723-10730, April 16, 1999
From the Department of Medicine, Cedars-Sinai Research Institute,
UCLA School of Medicine, Los Angeles, California 90048
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. However, molecular
mechanisms for this induction remain elusive. We therefore developed
ACTH-secreting AtT20 transformants for wild-type or mutated STAT3, a
cytokine signaling molecule, to address whether STAT3 is a determinant of LIF-mediated ACTH regulation. We show that these mutants act in a
dominant negative manner by blocking endogenous STAT3 tyrosine phosphorylation or STAT3 DNA binding. Attenuation of STAT3 activity in
the dominant negative AtT20 clones prevented LIF from promoting transcriptional activation of the 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, wild-type or dominant negative
STAT3-overexpressing clones showed comparable (4-fold) POMC induction
after treatment with cyclic adenosine monophosphate (cAMP), an
alternate inducer of POMC transcription, indicating the STAT3
specificity for LIF signaling. Moreover, dominant negative inactivation
of STAT3 activity resulted in abrogation of LIF-induced POMC mRNA
levels and ACTH secretion, confirming the in vivo 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 critical intrapituitary component of the LIF-mediated
neuroimmunoendocrine interface in corticotroph cells.
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