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Leukemia Inhibitory Factor Regulates Proopiomelanocortin Transcription a
Author(s) -
RAY DAVID W.,
REN SONGGUANG,
MELMED SHLOMO
Publication year - 1998
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1998.tb09560.x
Subject(s) - leukemia inhibitory factor , medicine , endocrinology , proopiomelanocortin , phosphorylation , chemistry , corticotropic cell , receptor , forskolin , signal transduction , inhibitory postsynaptic potential , pituitary gland , microbiology and biotechnology , biology , cytokine , hormone , interleukin 6
A bstract : Leukemia inhibitory factor (LIF), a pleiotropic cytokine, is expressed in both fetal and adult pituitary tissue, and LIF immunoreactivity is found in functional human pituitary tumors. LIF induces basal, and augments CRH‐induced, POMC mRNA and ACTH secretion from AtT20 cells. Therefore, we examined LIF signaling and LIF regulation of POMC expression in AtT20 cells. Immunoneutralization studies demonstrated the dependence of LIF action on both the specific LIF receptor (35% inhibition; p < 0.05) and also the gpl30 affinity converter (41% inhibition; p < 0.05). These antisera also attenuate basal ACTH secretion without added LIF. LIF rapidly induced tyrosyl phosphorylation of both STAT lα, and STATβ and also induced phosphorylation of a novel STAT lα related protein p115. LIF induced POMC transcription (−706/+64) and strikingly potentiated CRH action (up to 18‐fold induction). This synergy involved cAMP‐dependent pathways, as forskolin action was also potentiated by LIF. Deletion of the major CRH‐responsive region in POMC (‐323/‐166) abolished both CRH and LIF action on POMC transcription. Thus LIF action in pituitary corticotrophs is dependent on LIF receptor heterodimerisation with gpl30 and involves STAT protein tyrosyl phosphorylation. LIF enhances POMC transcription and strongly potentiates the well‐documented action of CRH on the POMC gene. These results define a subcellular mechanism for an immuno‐neuroendocrine interface between peripheral afferent signals and the HPA axis.