Cell-specific pituitary gene expression profiles after treatment with leukemia inhibitory factor reveal novel modulators for proopiomelanocortin expression.
Leukemia inhibitory factor (LIF) mediates the hypothalamo-pituitary-adrenal stress response. Transgenic mice overexpressing LIF in the developing pituitary have altered pituitary differentiation with expansion of corticotropes, maintenance of Rathke's cleft cysts, and suppression of all other pituitary cell types. Affymetrix GeneChips were used to identify modulators of LIF effects in corticotrope (AtT-20) and somatolactotrope (GH(3)) cells. In addition to genes known to respond to LIF in corticotrope cells [e.g. suppressor of cytokine signaling-3 (SOCS-3), signal transducer and activator of transcription-3, SH2 domain-containing tyrosine phosphatase-1, and proopiomelanocortin (POMC)], corticotrope-specific changes were also observed for genes involved in glycolysis and gluconeogenesis, transcription factors, signaling molecules, and expressed sequence tags. Two transcription factors identified, CCAAT/enhancer-binding protein beta (C/EBPbeta) and glial cell-derived neurotrophic factor (GDNF)-inducible factor (GIF), dose-dependently induced expression of the rat POMC promoter when overexpressed in AtT-20 cells. LIF further induced POMC transcription with C/EBPbeta, but not with GIF. C/EBPbeta also induced expression of the SOCS-3 promoter that was further enhanced by cotreatment with LIF. However, GIF did not affect SOCS-3 expression. These results indicate that C/EBPbeta and GIF are downstream effectors of LIF corticotrope action. LIF also stimulates the expression of inhibitors of its actions, such as SOCS-3 and SH2 domain-containing tyrosine phosphatase-1. alpha(2)-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFbeta/bone morphogenic protein signaling, was induced by LIF in a signal transducer and activator of transcription-3-dependent fashion. Pretreatment with AHSG/fetuin blocked LIF-induced expression of the POMC promoter independently of SOCS-3. Thus, using GeneChips, C/EBPbeta and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.
Division of Endocrinology, Department of Medicine, Cedars Sinai Medical Center, Los Angeles, CA 90048, USA.
Rula A
RA
Abbud
Robert
R
Kelleher
Shlomo
S
Melmed
D000324:Adrenocorticotropic Hormone / Q000096:biosynthesis; D000818:Animals; D001798:Blood Proteins / Q000235:genetics / Q000494:pharmacology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006019:Glycolysis; D013006:Growth Hormone / Q000096:biosynthesis; D015850:Interleukin-6 / Q000494:pharmacology*; D053605:Leukemia Inhibitory Factor; D010902:Pituitary Gland / Q000737:chemistry / Q000166:cytology / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000235:genetics*; D011388:Prolactin / Q000096:biosynthesis; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D012097:Repressor Proteins / Q000235:genetics; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics; D014162:Transfection; D060749:alpha-2-HS-Glycoprotein
C556357:Ahsg protein, mouse; D001798:Blood Proteins; D022782:CCAAT-Enhancer-Binding Protein-beta; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C491410:Socs3 protein, rat; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D060749:alpha-2-HS-Glycoprotein; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D011388:Prolactin; D013006:Growth Hormone