scholarly journals Reversal of Glucocorticoids-Dependent Proopiomelanocortin Gene Inhibition by Leukemia Inhibitory Factor

Endocrinology ◽  
2007 ◽  
Vol 148 (1) ◽  
pp. 422-432 ◽  
Author(s):  
Olivier Latchoumanin ◽  
Vanessa Mynard ◽  
Jocelyne Devin-Leclerc ◽  
Marie-Annick Dugué ◽  
Xavier Bertagna ◽  
...  
Keyword(s):  
Cell Line ◽  
Leukemia Inhibitory Factor ◽  
Molecular Mechanisms ◽  
Gene Promoter ◽  
Inhibitory Factor ◽  
Wild Type ◽  
Response Element ◽  
Synergistic Activation ◽  
Pomc Gene ◽  
Wild Type Promoter

We previously have described molecular mechanisms converging at the Nur response element-signal transducer and activator of transcription (STAT) composite site responsible for synergistic activation of the proopiomelanocortin (POMC) gene promoter by leukemia inhibitory factor (LIF) and CRH. In this study, we asked how glucocorticoids (GC), the physiological negative regulators of POMC gene expression, modulate this synergism. In the corticotroph cell line AtT-20, the response of the wild-type promoter to LIF+CRH was barely inhibited by GC, whereas a distal promoter subregion (−414/−293) encompassing the Nur response element-STAT site and devoid of the negative GC-responsive element located in the proximal domain, displayed a cooperative response to LIF + dexamethasone (DEX) and LIF+CRH+DEX treatments. LIF+CRH-stimulated ACTH secretion was also inefficiently inhibited by DEX in the same cell line. This study was focused thereafter on LIF+DEX cooperativity, which may be responsible, on the wild-type promoter, for lack of negative regulation by DEX of the LIF+CRH synergy. The STAT1–3 low-affinity site, in the context of the (−414/−293) subregion of the POMC promoter, was found necessary and sufficient for transcriptional synergism between activated GC receptor (GR) and STAT1–3. Moreover the activities of reporters specific for STAT1–3 or GR were reciprocally enhanced by DEX or LIF. Single and sequential chromatin immunoprecipitations revealed 1) a STAT-dependent corecruitment of coactivators after LIF and LIF+DEX stimulation and 2) a more lasting recruitment of both STAT3 and GR in the same enhanceosome on the endogenous POMC promoter after LIF+DEX joint stimulation than after the single one. Such events may be responsible for a lack of repressive property of GR unmasked on the whole POMC promoter during LIF+CRH stimulation and may contribute to the tonicity of the hypothalamic-pituitary-adrenal axis during inflammatory-infectious diseases.

scholarly journals Molecular analysis of ethyl methanesulfonate-induced reversion of a chromosomally integrated mutant shuttle vector gene in mammalian cells.

1988 ◽  
Vol 8 (10) ◽  
pp. 4185-4189 ◽  
Author(s):  
J A Greenspan ◽  
F M Xu ◽  
R L Davidson
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Dna Sequences ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Shuttle Vector ◽  
Ethyl Methanesulfonate ◽  
Wild Type ◽  
Single Base ◽  
Type Sequence

The molecular mechanisms of ethyl methanesulfonate-induced reversion in mammalian cells were studied by using as a target a gpt gene that was integrated chromosomally as part of a shuttle vector. Murine cells containing mutant gpt genes with single base changes were mutagenized with ethyl methanesulfonate, and revertant colonies were isolated. Ethyl methanesulfonate failed to increase the frequency of revertants for cell lines with mutant gpt genes carrying GC----AT transitions or AT----TA transversions, whereas it increased the frequency 50-fold to greater than 800-fold for cell lines with mutant gpt genes carrying AT----GC transitions and for one cell line with a GC----CG transversion. The gpt genes of 15 independent revertants derived from the ethyl methanesulfonate-revertible cell lines were recovered and sequenced. All revertants derived from cell lines with AT----GC transitions had mutated back to the wild-type gpt sequence via GC----AT transitions at their original sites of mutation. Five of six revertants derived from the cell line carrying a gpt gene with a GC----CG transversion had mutated via GC----AT transition at the site of the original mutation or at the adjacent base in the same triplet; these changes generated non-wild-type DNA sequences that code for non-wild-type amino acids that are apparently compatible with xanthine-guanine phosphoribosyltransferase activity. The sixth revertant had mutated via CG----GC transversion back to the wild-type sequence. The results of this study define certain amino acid substitutions in the xanthine-guanine phosphoribosyltransferase polypeptide that are compatible with enzyme activity. These results also establish mutagen-induced reversion analysis as a sensitive and specific assay for mutagenesis in mammalian cells.

Leukemia inhibitory factor (LIF) modulates pro-opiomelanocortin (POMC) gene regulation in stably transfected AtT-20 cells overexpressing LIF

Endocrine ◽  
1997 ◽  
Vol 7 (3) ◽  
pp. 325-330 ◽  
Author(s):  
Qiao-ling Li ◽  
Hiroki Yano ◽  
Song-Guang Ren ◽  
Xian Li ◽  
Theodore C. Friedman ◽  
...  
Keyword(s):  
Gene Regulation ◽  
Leukemia Inhibitory Factor ◽  
Inhibitory Factor ◽  
Pomc Gene

Levonorgestrel Inhibits Embryo Attachment by Eliminating Uterine Induction of Leukemia Inhibitory Factor

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Mitsunori Matsuo ◽  
Yasushi Hirota ◽  
Yamato Fukui ◽  
Hidetoshi Fujita ◽  
Tomoko Saito-Fujita ◽  
...  
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Embryo Implantation ◽  
Infertility Treatment ◽  
Vehicle Control ◽  
Inhibitory Factor ◽  
Wild Type ◽  
Attachment Sites ◽  
Attachment Inhibition ◽  
Evening Administration ◽  
Embryo Attachment

Abstract Progestogens including progesterone (P4) and levonorgestrel (LNG) are clinically used for multiple purposes such as contraception and infertility treatment. The effects of progestogens on the uterus remains to be elucidated. Here we examine the effect of excessive progestogen administration on embryo implantation focusing on the function of uterine leukemia inhibitory factor (LIF), a cytokine that is induced by estrogen and essential for embryo attachment. Treatment of wild-type (WT) female mice with vehicle (control), LNG at the dose of 300 μg/kg/day and P4 at the dose of 10 mg/day from day 1 to day 4 of pregnancy was conducted. LNG-treated and P4-treated mice showed embryo attachment failure on day 5 of pregnancy (The rate of mice with embryo attachment sites [%MAS], 11% and 13%, respectively), while all the control mice had normal attachment sites. Uterine LIF expression was significantly reduced in LNG-treated and P4-treated mice on day 4 evening. Administration of recombinant LIF (rLIF) at the dose of 24 μg/day on day 4 significantly rescued embryo attachment failure in LNG-treated and P4-treated mice (%MAS, 80% and 75%, respectively). Estradiol (E2) administration also rescued embryo attachment failure in LNG-treated mice (%MAS, 83%). Furthermore, excess P4 treatment before implantation decreased decidual P4 receptor (PGR) expression and induced decidualization defect apart from LIF downregulation. These findings indicate that progestogens cause embryo attachment inhibition through downregulation of uterine LIF expression and compromised decidualization through downregulation of PGR independently of LIF reduction. This study may contribute to a better understanding of contraceptive action of progestogens.

scholarly journals Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation

2003 ◽  
Vol 179 (1) ◽  
pp. 15-23 ◽  
Author(s):  
JA Baugh ◽  
SC Donnelly
Keyword(s):  
Inflammatory Response ◽  
Migration Inhibitory Factor ◽  
Macrophage Migration Inhibitory Factor ◽  
Molecular Mechanisms ◽  
Adaptive Immune Response ◽  
Gene Promoter ◽  
Chronic Inflammatory Disease ◽  
Inhibitory Factor ◽  
Macrophage Migration ◽  
Promoter Polymorphisms

The diverse actions of macrophage migration inhibitory factor (MIF) within the immuno-neuroendocrine system are yet to be fully understood, but it is clear that MIF plays a pivotal role in the regulation of both the innate and adaptive immune response. An emerging body of data presently indicates that MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control the 'set point' and magnitude of the immune and inflammatory response. In this article we will review the actions of MIF within the immune system and discuss the overlapping and contrasting aspects of MIF and glucocorticoid biology. In particular we will focus on the role of MIF within the immuno-neuroendocrine interface and suggest molecular mechanisms by which MIF may counter-regulate glucocorticoid function. Finally we will discuss emerging evidence that functional MIF gene-promoter polymorphisms render one susceptible to elevated MIF expression, and the development of an exaggerated immune/inflammatory response that potentiates the progression to chronic inflammatory disease.

scholarly journals Mutation of a palmitoyltransferase ZDHHC18-like gene is responsible for the minute wing mutation in the silkworm (Bombyx mori)

2017 ◽  
Author(s):  
Ye Yu ◽  
Xiaojing Liu ◽  
Xiao Ma ◽  
Zhongjie Zhang ◽  
Na Liu ◽  
...  
Keyword(s):  
Bombyx Mori ◽  
Positional Cloning ◽  
Molecular Mechanisms ◽  
Adult Stage ◽  
Significant Proportion ◽  
Gene Promoter ◽  
Wild Type ◽  
Evolutionarily Conserved ◽  
In The Wild ◽  
Hippo Signalling

AbstractPulpal- and adult-stage minute wing (mw) mutants of the silkworm Bombyx mori have much smaller wings than those of the wild type. Herein, we report the genetic and molecular mechanisms underling the formation of the minute wing. Fine mapping and positional cloning revealed that a palmitoyltransferase ZDHHC18-like gene (BmAPP）was responsible for the mw mutation. CRISPR/Cas9 screening of the BmAPP gene in wild-type embryos revealed that a significant proportion of adults had the mw mutation. In an mw mutant strain, u11, a 10-bp insertion in the promoter of a novel gene resulted in low-level translation of a protein belonging to the DHHC family. A PiggyBac-based transgenic analysis showed that the promoter induced the expression of aBmAPP gene promoter in the wild type but not the mw mutant. These findings indicate that functional deletion of this gene promoter accounts for the mw mutation in silkworm. The possibility that BmAPP gene is involved in Hippo signalling pathway, an evolutionarily conserved signaling pathway that controls organ size, is discussed.

scholarly journals Molecular mechanisms that control expression of the B lymphocyte antigen receptor complex.

1995 ◽  
Vol 181 (1) ◽  
pp. 161-168 ◽  
Author(s):  
S A Grupp ◽  
R N Mitchell ◽  
K L Schreiber ◽  
D J McKean ◽  
A K Abbas
Keyword(s):  
B Cell ◽  
Cell Line ◽  
Heavy Chain ◽  
Molecular Mechanisms ◽  
B Lymphocyte ◽  
Cell Receptor ◽  
Surface Expression ◽  
Wild Type ◽  
Membrane Immunoglobulin ◽  
Negative Cell Line

The B cell receptor for antigen (BCR) is a complex of membrane immunoglobulin (mIg) and at least two other proteins, Ig alpha (mb-1) and Ig beta (B29). This complex promotes surface expression of the BCR and acts to transduce an activation signal. We have used a system of mu heavy chain constructs transfected into murine B cell lines to probe structure-function relationships in the BCR complex. One mutant mu chain, in which two polar transmembrane residues (Tyr587, Ser588) are replaced with valine, fails to associate with Ig alpha and Ig beta and is incapable of transducing signals as a result of mIg cross-linking. This mutant is expressed on the surface at high levels when transfected into a plasmacytoma line that lacks Ig alpha, whereas wild-type mu is retained in this cell line in the endoplasmic reticulum. Pulse-chase and immunoprecipitation analyses indicate that the mutant is more rapidly released from calnexin than the wild-type mu. Further, transfection of Ig alpha into this Ig alpha-negative cell line allows release of the mu chain from calnexin and surface expression of the BCR. These results identify the transmembrane residues of mu heavy chain that control binding to calnexin and Ig alpha, and suggest that calnexin-dependent intracellular retention is an important control mechanism for expression of the BCR complex.

scholarly journals Decreased Activity of the Ghrhr and Gh Promoters Causes Dominantly Inherited GH Deficiency in Humanized GH1 Mouse Models

Endocrinology ◽  
2019 ◽  
Vol 160 (11) ◽  
pp. 2673-2691
Author(s):  
Daisuke Ariyasu ◽  
Emika Kubo ◽  
Daisuke Higa ◽  
Shinsuke Shibata ◽  
Yutaka Takaoka ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Gh Deficiency ◽  
Gene Promoter ◽  
Dominant Negative ◽  
Hormone Deficiency ◽  
Dominant Negative Effect ◽  
Wild Type ◽  
New Paradigm ◽  
Gh Secretion

Abstract Isolated growth hormone deficiency type II (IGHD2) is mainly caused by heterozygous splice-site mutations in intron 3 of the GH1 gene. A dominant-negative effect of the mutant GH lacking exon 3 on wild-type GH secretion has been proposed; however, the molecular mechanisms involved are elusive. To uncover the molecular systems underlying GH deficiency in IGHD2, we established IGHD2 model mice, which carry both wild-type and mutant copies of the human GH1 gene, replacing each of the endogenous mouse Gh loci. Our IGHD2 model mice exhibited growth retardation along with intact cellular architecture and mildly activated endoplasmic reticulum stress in the pituitary gland, caused by decreased GH-releasing hormone receptor (Ghrhr) and Gh gene promoter activities. Decreased Ghrhr and Gh promoter activities were likely caused by reduced levels of nuclear CREB3L2, which was demonstrated to stimulate Ghrhr and Gh promoter activity. To our knowledge, this is the first in vivo study to reveal a novel molecular mechanism of GH deficiency in IGHD2, representing a new paradigm that differs from widely accepted models.

scholarly journals Leukemia-Inhibitory Factor—Neuroimmune Modulator of Endocrine Function*

2000 ◽  
Vol 21 (3) ◽  
pp. 313-345 ◽  
Author(s):  
C. J. Auernhammer ◽  
S. Melmed
Keyword(s):  
Leukemia Inhibitory Factor ◽  
Energy Homeostasis ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Bone Cell ◽  
Janus Kinase ◽  
Inhibitory Factor ◽  
Endocrine Function ◽  
Cytokine Signaling ◽  
Endocrine Regulation

Abstract Leukemia-inhibitory factor (LIF) is a pleiotropic cytokine expressed by multiple tissue types. The LIF receptor shares a common gp130 receptor subunit with the IL-6 cytokine superfamily. LIF signaling is mediated mainly by JAK-STAT (janus-kinase-signal transducer and activator of transcription) pathways and is abrogated by the SOCS (suppressor-of cytokine signaling) and PIAS (protein inhibitors of activated STAT) proteins. In addition to classic hematopoietic and neuronal actions, LIF plays a critical role in several endocrine functions including the utero-placental unit, the hypothalamo-pituitary-adrenal axis, bone cell metabolism, energy homeostasis, and hormonally responsive tumors. This paper reviews recent advances in our understanding of molecular mechanisms regulating LIF expression and action and also provides a systemic overview of LIF-mediated endocrine regulation. Local and systemic LIF serve to integrate multiple developmental and functional cell signals, culminating in maintaining appropriate hormonal and metabolic homeostasis. LIF thus functions as a critical molecular interface between the neuroimmune and endocrine systems.

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