scholarly journals Cell-Specific Pituitary Gene Expression Profiles after Treatment with Leukemia Inhibitory Factor Reveal Novel Modulators for Proopiomelanocortin Expression

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 867-880 ◽  
Author(s):  
Rula A. Abbud ◽  
Robert Kelleher ◽  
Shlomo Melmed
Keyword(s):  
Transcription Factors ◽  
Leukemia Inhibitory Factor ◽  
Expression Profiles ◽  
Tyrosine Phosphatase ◽  
Sh2 Domain ◽  
Inhibitory Factor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Induced Expression ◽  
Transcription 3

Abstract 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 (GH3) 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 β (C/EBPβ) 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/EBPβ, but not with GIF. C/EBPβ 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/EBPβ 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. α2-HS-glycoprotein (AHSG)/fetuin, a secreted protein that antagonizes bone TGFβ/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/EBPβ and GIF have been identified as novel mediators and AHSG/fetuin as an inhibitor of LIF action in corticotropes.

Leukemia inhibitory factor promotes porcine oocyte maturation and is accompanied by activation of signal transducer and activator of transcription 3

2013 ◽  
Vol 81 (3) ◽  
pp. 230-239 ◽  
Author(s):  
Thanh Quang Dang-Nguyen ◽  
Seiki Haraguchi ◽  
Kazuhiro Kikuchi ◽  
Tamás Somfai ◽  
Szilárd Bodó ◽  
...  
Keyword(s):  
Oocyte Maturation ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Signal Transducer ◽  
Porcine Oocyte ◽  
Transcription 3

scholarly journals Feedback Inhibition of Leptin Receptor/Jak2 Signaling via Tyr1138 of the Leptin Receptor and Suppressor of Cytokine Signaling 3

2005 ◽  
Vol 19 (4) ◽  
pp. 925-938 ◽  
Author(s):  
Sarah L. Dunn ◽  
Marie Björnholm ◽  
Sarah H. Bates ◽  
Zhibin Chen ◽  
Matthew Seifert ◽  
...  
Keyword(s):  
Rna Interference ◽  
Leptin Receptor ◽  
Feedback Inhibition ◽  
Sh2 Domain ◽  
Erythropoietin Receptor ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Suppressor Of Cytokine Signaling ◽  
Leptin Sensitivity ◽  
Transcription 3

Abstract Leptin is an adipocyte-derived hormone that communicates the status of body energy stores to the brain to regulate feeding and energy balance. The inability of elevated leptin levels to adequately suppress feeding in obesity suggests attenuation of leptin action under these conditions; the activation of feedback circuits due to high leptin levels could contribute to this leptin resistance. Using cultured cells exogenously expressing the long form of the leptin receptor (LRb) or an erythropoietin receptor/LRb chimera, we show that chronic stimulation results in the attenuation of LRb signaling and the establishment of a state in which the receptor is refractory to reactivation. Mutation of LRb Tyr1138 (the site that recruits signal transducer and activator of transcription 3) alleviated this feedback inhibition, suggesting that signal transducer and activator of transcription 3 mediates the induction of a feedback inhibitor, such as suppressor of cytokine signaling 3 (SOCS3), during chronic LRb stimulation. Indeed, manipulation of the expression or activity of the LRb-binding tyrosine phosphatase, SH2-domain containing phosphatase-2, by overexpression of wild-type and dominant negative isoforms or RNA interference-mediated knockdown did not alter the attenuation of LRb signals. In contrast, SOCS3 overexpression repressed LRb signaling, whereas RNA interference-mediated knockdown of SOCS3 resulted in increased LRb signaling that was not attenuated during chronic ligand stimulation. These data suggest that Tyr1138 of LRb and SOCS3 represent major effector pathways for the feedback inhibition of LRb signaling. Furthermore, we show that mice expressing an LRb isoform mutant for Tyr1138 display increased activity of the leptin-dependent growth and immune axes, suggesting that Tyr1138-mediated feedback inhibition may regulate leptin sensitivity in vivo.

Uterine epithelial LIF receptors contribute to implantation chamber formation in blastocyst attachment

Endocrinology ◽  
2021 ◽  
Author(s):  
Yamato Fukui ◽  
Yasushi Hirota ◽  
Tomoko Saito-Fujita ◽  
Shizu Aikawa ◽  
Takehiro Hiraoka ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Leukemia Inhibitory Factor ◽  
Ovarian Hormones ◽  
Signal Transducer ◽  
Blastocyst Implantation ◽  
Implantation Process ◽  
Uterine Glands ◽  
Transcription 3

Abstract Recent studies have demonstrated that the formation of an implantation chamber composed of a uterine crypt, an implantation-competent blastocyst, and uterine glands is a critical step in blastocyst implantation in mice. Leukemia inhibitory factor (LIF) activates signal transducer and activator of transcription 3 (STAT3) precursors via uterine LIF receptors (LIFRs), allowing successful blastocyst implantation. Our recent study revealed that the role of epithelial STAT3 is different from that of stromal STAT3. However, both are essential for blastocyst attachment, suggesting the different roles of epithelial and stromal LIFR in blastocyst implantation. However, how epithelial and stromal LIFR regulate the blastocyst implantation process remains unclear. To investigate the roles of LIFR in the uterine epithelium and stroma, we generated Lifr-floxed/lactoferrin (Ltf)-iCre (Lifr eKO) and Lifr-floxed/anti-Mullerian hormone receptor type 2 (Amhr2)-Cre (Lifr sKO) mice with deleted epithelial and stromal LIFR, respectively. Surprisingly, fertility and blastocyst implantation in the Lifr sKO mice were normal despite stromal STAT3 inactivation. In contrast, blastocyst attachment failed, and no implantation chambers were formed in the Lifr eKO mice with epithelial inactivation of STAT3. In addition, normal responsiveness to ovarian hormones was observed in the peri-implantation uteri of the Lifr eKO mice. These results indicate that the epithelial LIFR-STAT3 pathway initiates the formation of implantation chambers, leading to complete blastocyst attachment, and that stromal STAT3 regulates blastocyst attachment without stromal LIFR control. Thus, uterine epithelial LIFR is critical to implantation chamber formation and blastocyst attachment.

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