Leukemia inhibitory factor regulates proopiomelanocortin transcription.
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 1 alpha, and STAT beta and also induced phosphorylation of a novel STAT 1 alpha 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.
Ray
D W
DW
Department of Medicine, Cedars-Sinai Research Institute-UCLA School of Medicine 90048, USA.
Ren
S G
SG
Melmed
S
S
D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism; D006131:Growth Inhibitors / Q000494:pharmacology / Q000502:physiology*; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines / Q000494:pharmacology / Q000502:physiology*; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D010766:Phosphorylation; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000187:drug effects / Q000235:genetics*; D018121:Receptors, Cytokine / Q000502:physiology; D053606:Receptors, OSM-LIF; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D052118:Lysosomal-Associated Membrane Protein 1
D000324:Adrenocorticotropic Hormone; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D053680:Leukemia Inhibitory Factor Receptor alpha Subunit; D008222:Lymphokines; D051907:Lysosomal Membrane Proteins; D008562:Membrane Glycoproteins; D011333:Pro-Opiomelanocortin; D018121:Receptors, Cytokine; D053606:Receptors, OSM-LIF; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; C489116:LAMP1 protein, human; D052118:Lysosomal-Associated Membrane Protein 1; C507837:LIF protein, human; C507840:LIFR protein, human; C052255:Lamp1 protein, mouse; C507838:Lif protein, mouse; C507841:Lifr protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse