Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PRL is synthesized by decidualized endometrial stromal cells from the midsecretory phase in a nonconception cycle and throughout pregnancy. The exact role of PRL in the human endometrium remains to be elucidated; however, the pattern of expression supports a role for PRL during implantation and placentation. This study investigated the site and pattern of expression of PRL receptors in the nonpregnant human endometrium. In situ hybridization and immunohistochemistry localized expression of the receptor in the glandular epithelium and a subset of stromal cells of the endometrium. As judged by the intensity of staining, expression of the receptor was dramatically up-regulated during the secretory phase. Expression of the PRL receptor gene in the endometrium from the secretory phase of the menstrual cycle was confirmed by ribonuclease protection assay using 50 micrograms total ribonucleic acid. Phosphorylation of Janus kinase-2 (JAK2), STAT1 (signal transducer and activator of transcription-1), and STAT5 proteins in response to PRL was investigated to establish the signaling pathway of PRL in the human endometrium. Endometrial tissue was collected during the secretory phase of the menstrual cycle and incubated in the presence of 100 ng/mL human PRL for 0, 5, 10, and 20 min. JAK2 phosphorylation was induced by PRL at 5 min, whereas STAT1 and STAT5 phosphorylation was apparent 20 min after stimulation with PRL. Immunohistochemistry localized the JAK/STAT proteins in the glandular epithelial cells and a subset of stromal cells, as was observed for the PRL receptor. Secretory phase stromal and glandular cells cultured separately and in the presence or absence of 100 ng/mL PRL confirmed the PRL-induced phosphorylation of JAK2/STAT proteins, at least in the glandular compartment. These studies demonstrate an up-regulation of expression of functional PRL receptors during the secretory phase of the menstrual cycle. Further, decidual PRL through a paracrine mechanism may influence glandular epithelial function/secretions and direct gene transcription through the JAK/STAT pathway. The target genes activated by PRL in the glandular epithelium of the nonpregnant human endometrium remain to be elucidated.
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PMID:Expression of functional prolactin receptors in nonpregnant human endometrium: janus kinase-2, signal transducer and activator of transcription-1 (STAT1), and STAT5 proteins are phosphorylated after stimulation with prolactin. 966 41

Pituitary corticotroph SOCS-3 is a novel intracellular regulator of leukemia inhibitory factor (LIF)-mediated proopiomelanocortin gene expression and adrenocorticotropic hormone (ACTH) secretion, inhibiting LIF-activated Janus kinase-signal transducers and activators of transcription (STAT) signaling in a negative autoregulatory loop. We now demonstrate in corticotroph AtT-20 cells that LIF-stimulated endogenous SOCS-3 mRNA expression is blocked in stable transfectants of SOCS-3 wild type or in dominant negative STAT-3 mutants, respectively. We characterized approximately 3.8-kb genomic 5' sequence of murine SOCS-3, including approximately 2.9-kb sequence upstream of the transcription start site (+1), which was determined by 5' rapid amplification of cDNA ends and RNase protection assay. Different 5' constructs were cloned into the pGL3Basic vector, and luciferase activity was assayed in transiently transfected ACTH-secreting corticotroph AtT-20 cells. A STAT-1/STAT-3 binding element, located at nucleotides -72 to -64, was essential for LIF stimulation of SOCS-3 promoter activity. LIF induced 10-fold increased luciferase activity in a wild-type construct spanning -2757 to +929 bases. However, deletion or point mutation of the STAT-1/STAT-3 binding element abrogated LIF action (2- to 3-fold). Electrophoretic mobility-shift assay analysis confirmed specific binding of STAT-1 and STAT-3 to this region. These results characterize the genomic 5' region of murine SOCS-3 and identify an important STAT-1/STAT-3 binding element therein. Thus, LIF-stimulated SOCS-3 gene expression is at least in part mediated by STAT-3 and STAT-1. The cytokine inhibitor SOCS-3 acts in a negative loop to autoregulate its own gene expression, thus limiting its accumulation in the corticotroph cell. These results demonstrate a mechanism for corticotroph plasticity with rapid "on" and "off" ACTH induction in response to neuro-immuno-endocrine stimuli, such as LIF.
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PMID:Autoregulation of pituitary corticotroph SOCS-3 expression: characterization of the murine SOCS-3 promoter. 1035 22

PRL expression in the human uterus is up-regulated during the mid to late secretory phase of the menstrual cycle. This coincides with up-regulation of the expression of the PRL receptor, which is localized primarily to the endometrial glandular epithelial cells. Recent data have demonstrated activation of the Jak (Janus kinase)/Stat (signal transducer and activator of transcription) signaling pathway in the secretory endometrium after stimulation with exogenous PRL. However, the target genes for the action of PRL on the endometrial epithelial cells have not been elucidated. In this study we have investigated the pattern/site of expression of the transcription factor interferon regulatory factor-1 (IRF-1) as well as the effect of exogenous PRL on the transcription of IRF-1 in the human endometrium during the mid to late secretory phase of the menstrual cycle. Expression of the IRF-1 gene was confirmed by RNase protection assays using a 260-bp homologous [alpha-32P]UTP-labeled IRF-1 complementary ribonucleic acid (RNA) probe and 10 microg total RNA extracted from human endometrium (n = 5) collected between days 19 and 26 of the menstrual cycle. Northern and Western blot analyses were conducted on secretory phase human endometrium (n = 3) using human [alpha-32P]dCTP-labeled IRF-1 complementary DNA and antihuman IRF-1 antibody. Expression of the IRF-1 gene in the secretory phase endometrium was encoded by a RNA transcript of approximately 2.1 kb and a protein of 48 kDa. Furthermore, expression of the IRF-1 gene in the secretory phase endometrium was localized by immunohistochemistry predominantly to the glandular epithelial cells as has been shown previously for the PRL receptor. To investigate the effect of PRL on expression of IRF-1, human endometrial biopsies (n = 3) collected between days 24-26 of the menstrual cycle were cultured in the presence of cycloheximide with or without 100 ng/mL human PRL for 2 and 4 h. Culture of endometrial tissue with PRL for 2 and 4 h resulted in 2.9 +/- 0.3-fold (P < 0.01) and 1.7 +/- 0.1-fold induction of expression of the IRF-1 gene, respectively. These data demonstrate the expression of the transcription factor IRF-1 in the glandular epithelium of the endometrium and its regulation by PRL during the secretory phase of the menstrual cycle. Previous observations of the temporal up-regulation of expression of both PRL and PRL receptors in the secretory human endometrium and their localization to the stromal and glandular compartments, respectively, suggest that endometrial PRL mediates transcription of the IRF-1 gene in a paracrine fashion.
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PMID:Localization of interferon regulatory factor-1 (IRF-1) in nonpregnant human endometrium: expression of IRF-1 is up-regulated by prolactin during the secretory phase of the menstrual cycle. 1056 82

This study investigated the expression and signaling pathway of PRL and its receptor in the non-pregnant uterus of the common marmoset monkey. Immunohistochemistry localized PRL expression to the stromal compartment of the endometrium. Expression was minimal during the proliferative phase and was up-regulated during the mid to late secretory phase of the ovulatory cycle. In situ hybridization and immunohistochemistry localized expression of the PRL receptor to the glandular epithelium of the endometrium. Similar to that of PRL, PRL receptor expression was minimal during the proliferative phase and was dramatically up-regulated during the secretory phase. The temporal pattern of PRL receptor gene expression in the marmoset uterus across the cycle was further confirmed by ribonuclease protection assay. The roles of Janus kinase-2 (JAK2) and signal transducer and activator of transcription-1 (STAT1) in the intracellular signaling pathway of PRL were also assessed in the mid to late secretory phase. JAK2/STAT1 proteins were localized in the glandular epithelial compartment, and both proteins were temporally phosphorylated in response to PRL. Finally, the pattern of expression of the interferon regulatory factor-1 (IRF-1) gene and the effect of PRL on transcription of IRF-1 were investigated during the mid to late secretory phase. IRF-1 expression in the marmoset uterus was encoded by a protein of 48 kDa and was localized to the glandular epithelial compartment, as was observed for the PRL receptor and JAK2/STAT1 proteins. Moreover, incubation of mid to late secretory uterine tissue with PRL for 1 and 3 h resulted in 0.4 +/- 0.2- and 2.4 +/-0.5-fold (P < 0.05) inductions of the IRF-1 gene, respectively. These studies confirm the expression of both PRL and its receptor in the uterus of the marmoset monkey. Expression of both genes is up-regulated during the mid to late secretory phase of the ovulatory cycle. PRL function in the marmoset uterus is linked to the JAK/STAT signaling pathway, leading to the regulation of expression of PRL-responsive genes such as IRF-1. The site of expression of PRL, PRL receptors, and IRF-1 in the marmoset uterus suggest that PRL may influence glandular epithelial function and direct gene transcription in these cells in a paracrine fashion.
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PMID:Localization and signaling of the prolactin receptor in the uterus of the common marmoset monkey. 1077 Feb 19

Removal of adrenal steroids by adrenalectomy (ADX) slows or reverses the development of many forms of obesity in rodents, including those that are leptin or leptin receptor deficient. Obesity is associated with hyperleptinemia and leptin resistance. We hypothesized that glucocorticoids impair leptin receptor signaling and that removal thereof would activate the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) signaling pathway. The inhibitory effect of leptin (2.5 microg icv) on food intake was enhanced in ADX rats. A combination of ribonuclease protection assays, RT-PCR, Western blots, and mobility shift assays was used to evaluate the leptin signaling pathway in whole hypothalami from sham-operated, ADX and corticosterone-replaced ADX (ADX-R) Sprague-Dawley rats that were treated acutely with either saline vehicle or leptin intracerebroventricularly. ADX increased the expression of leptin receptor mRNA, increased STAT-3 mRNA and protein levels, induced constitutive STAT-3 phosphorylation and DNA binding activity, and also reduced suppressor of cytokine signaling-3 (SOCS-3) mRNA and protein levels. ADX and leptin treatment increased STAT-3 phosphorylation, but with no concomitant increase in DNA binding activity. Leptin and ADX decreased NPY mRNA expression, but their combination did not further decrease NPY mRNA. Corticosterone supplementation of ADX rats partially reversed many of these effects. In conclusion, ADX through activation of STAT-3 and inhibition of SOCS-3 activates the JAK-STAT signaling pathway. These effects most probably explain the ability to prevent the development of obesity by removal of adrenal steroids.
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PMID:Constitutive activation of STAT-3 and downregulation of SOCS-3 expression induced by adrenalectomy. 1170 92

Leptin is a 16-kd hormone that mediates a range of metabolic effects by using a transduction pathway from the long form of the leptin receptor, OB-R(L,) through Janus kinase-signal transducer and activator of transcription (Jak-Stat) signaling components. Leptin is produced by hepatic stellate cells (HSCs) but only following their "activation." Because activation of stellate cells is a central event in the fibrotic response to liver injury, we hypothesized that leptin may directly stimulate fibrogenesis in activated stellate cells via OB-R(L). We analyzed leptin receptors and their signaling partners in a stellate cell line (HSC-T6) as well as in primary stellate cell isolates. We also examined the effect of leptin on stellate cell expression of alpha(2)(I) collagen messenger RNA (mRNA) levels by ribonuclease protection analysis (RPA). Finally, we examined the role of leptin in in vivo fibrogenesis by inducing a wounding response in ob/ob mice, which lack functional leptin. HSC-T6 and culture-activated stellate cells expressed OB-R(L). Scatchard analysis verified specific binding of leptin to HSCs, with an association constant (K(d)) equal to 660 +/- 5.8 pmol/L. Exposure of HSCs to leptin resulted in significant increases in alpha(2)(I) collagen mRNA expression. Transient transfection with a promoter reporter construct showed a 3-fold increase in alpha(2)(I) collagen transgene activity. Leptin stimulated activation of Stat3 in activated HSCs. Finally, lean animals, but not ob/ob littermates, had significant fibrosis as assessed by picrosirius red staining and abundant alpha-smooth muscle actin staining. In conclusion, these results indicate that leptin is profibrogenic in activated HSCs and can signal via the Jak-Stat pathway. Up-regulation of leptin signaling in liver injury could contribute to enhanced fibrogenesis, particularly in states in which leptin levels are high.
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PMID:Leptin in hepatic fibrosis: evidence for increased collagen production in stellate cells and lean littermates of ob/ob mice. 1191 21

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