Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is the adipocyte-specific product of the ob gene. Expression of leptin in fully fed animals reflects adipocyte size and body-fat mass. Leptin signals the status of body energy stores to the brain, where signals emanate to regulate food intake and whole-body energy expenditure. The leptin gene was identified in the leptin-deficient, obese ob/ob mouse by positional cloning techniques. Recently, leptin has been cloned in domestic species including pigs, cattle, and chickens. The leptin receptor has at least five splice variants; the long form of the receptor is primarily expressed in the hypothalamus and is thought to be the predominant signaling isoform. Leptin receptors are members of the cytokine family of receptors and signal via janus-activated kinases (JAK)/signal transducers and activators of transcription (STAT) and mitogen-activated protein kinase (MAPK) pathways. Mutations in the leptin or leptin receptor genes results in morbid obesity, infertility, and insulin resistance in rodents and humans. Leptin regulates food intake and energy expenditure via central and peripheral mechanisms. Leptin receptors are expressed in most tissues, and in vitro evidence suggests that leptin may have direct effects on some tissues such as adipose tissue, the adrenal cortex, and the pancreatic beta-cell. Leptin is thought to influence whole-body glucose homeostasis and insulin action. Studies are underway to determine the role that leptin plays in the biology of domestic animals.
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PMID:Leptin and its receptors: regulators of whole-body energy homeostasis. 986 38

The infertility phenotype of cyclooxygenase-2 (Cox-2)-deficient female mice establishes the important role of Cox-2 in pregnancy. Cox-2 deficiency results in defective ovulation, fertilization, implantation, and decidualization; the latter of which can be restored in part by the prostacyclin analog carbaprostacyclin. Uterine Cox-2 expression during early pregnancy shows distinct localization and kinetics in the uterine luminal epithelium and underlying stromal cells, suggesting that expression is tightly regulated. Several intracellular signaling cascades including ERK, p38, and JNK are implicated in vitro as critical components of regulated Cox-2 expression in response to mitogens, growth factors, and cytokines. We investigated the involvement of these signaling pathways during Cox-2 induction in vivo by monitoring uterine kinase activity after intraluminal application of a deciduogenic stimulus. Our results show that the ERK and p38 pathways are activated in uterine preparations as early as 5-min post-stimulation. ERK activation was sustained for several hours with a return to baseline levels by 4 h. p38 activation was rapid with a peak at 5-min post-stimulation and returned to near baseline levels after 45 min. Systemic administration of a MEK inhibitor completely inhibited ERK activation, but did not affect early (2 h) luminal epithelial or late (24 h) stromal Cox-2 expression and only modestly affected decidualization. In contrast, administration of a p38 inhibitor modestly inhibited early Cox-2 expression in the luminal epithelium, while dramatically diminishing late stromal expression. In parallel, induced stromal peroxisomal proliferator activated receptor-delta (PPARdelta) expression is blunted by p38 inhibition. p38 inhibition also significantly inhibited decidualization. These results suggest that p38, but not ERK, activation is required for induced Cox-2 and PPARdelta expression during decidualization. In addition, inhibition of p38 led to decreased decidualization suggesting that an intracrine prostanoid pathway consisting of Cox-2, prostacyclin, and PPARdelta is required for maintenance of early pregnancy.
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PMID:Regulation of cyclooxygenase-2 induction in the mouse uterus during decidualization. An event of early pregnancy. 1096 80

Endometriosis, a common gynecological disorder that causes infertility and pelvic pain, is defined as the presence of endometrial glands and stroma within extra-uterine sites. However, despite extensive studies its etiology and pathogenesis are not completely understood. Differentially expressed genes were investigated in epithelial and stromal cells from deep endometriosis and matched eutopic endometrium using cDNA microarrays and laser capture microdissection. Validation of results of several up- and down-regulated genes was performed by quantitative real-time RT-PCR. Our data showed that platelet-derived growth factor receptor alpha (PDGFRA), protein kinase C beta1 (PKC beta1) and janus kinase 1 (JAK1) were upregulated, and Sprouty2 and mitogen-activated protein kinase kinase 7 (MKK7) were downregulated in endometriosis stromal cells, suggesting the involvement of the RAS/RAF/MAPK signaling pathway through PDGFRA in endometriosis pathophysiology. In addition, two potential negative regulators of aromatase expression, chicken ovalbumin upstream promoter transcription factor 2 (COUP-TF2) and prostaglandin E2 receptor subtype EP3 (PGE2EP3), were downregulated in endometriosis epithelial cells, which might result in increased local production of estrogen in endometriosis epithelial cells. Furthermore, three potential candidate genes that might be involved in endometriosis related pain were identified: tyrosine kinase receptor B (TRkB) in endometriosis epithelial cells, and serotonin transporter (5HTT) and mu opioid receptor (MOR) in endometriosis stromal cells were all upregulated. One of the candidate genes, MOR, may be involved in a defective immune system in endometriosis. This study has provided new insights into endometriosis pathophysiology.
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PMID:DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. 1529 92

In utero exposure to chemicals with antiandrogen activity induces undescended testis, hypospadias, and sub- or infertility. The hypospermatogenesis observed in the adult rat testis exposed in utero to the antiandrogen flutamide has been reported to be a result of a long-term apoptotic cell death process in mature germ cells. However, little if anything is known about the upstream signaling mechanisms controlling this apoptosis. In the present study, we have investigated the possibility that the TGF-beta signaling pathway may be at play in this control of the apoptotic germ cell death process. By using a model of adult rat exposed in utero to 0, 0.4, 2, or 10 mg/kg.d flutamide, we observed that pro-TGF-beta signaling members, such as the three isoforms of TGF-beta ligands (TGF-beta1-3), the two TGF-beta receptors (TGF-betaRI and -RII) and the R-Smads Smad 1, Smad 2, Smad 3, and Smad 5 were inhibited at the mRNA and protein levels, whereas the anti-TGF-beta signaling member Smad 7 was overexpressed. Furthermore, we report that the overexpression of Smad 7 mRNA could induce an activation of c-Jun N-terminal kinase, because of the observed c-Jun overexpression, activation, and nuclear translocation leading to an increase in the transcription of the proapoptotic factor Fas-L. Together, the alterations of TGF-beta signaling may represent upstream mechanisms underlying the adult germ cell apoptotic process evidenced in adult rat testis exposed in utero to antiandrogenic compounds such as flutamide.
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PMID:Alteration of transforming growth factor-beta signaling system expression in adult rat germ cells with a chronic apoptotic cell death process after fetal androgen disruption. 1616 21

HSD-3.8 cDNA (accession number AF311312) encodes a human sperm component. A 0.7 kb fragment (HSD-0.7) containing three immunological epitopes of HSD-3.8 cDNA was prepared and expressed in E. coli. Immunization of female rats with the recombinant HSD-0.7 proteins induced infertility. A cDNA fragment encoding the C-terminal 144 amino acids of human G-protein beta l subunit (Gbeta1-C144) was screened by yeast two-hybrid, when HSD-0.7 segment was used as a bait. Recombinant His6-tagged-Gbeta1-C144 protein was expressed in E. coli BL21 and Anti-Gbeta1 serum was raised with purified Gbeta1-C144. HA-tagged HSD-0.7 and FLAG-tagged Gbeta1 plasmids were constructed and co-transfected into human embryonal kidney 293 cells. Two proteins were localized at superimposable sites in the cytoplasm, and they formed a complex when 500 micromol/L GDP existed. Overexpression of HSD-0.7 activated the G-protein-mediated extracellular signal-regulated kinases (ERK1/2); however, the truncated fragments of HSD-0.7, which lacked either TPR domain or P-loop, lost the ability to activate the ERK1/2 pathway. Further study revealed that the activation of ERK1/2 was protein kinase C (PKC) rather than Ras dependent. These results provide evidence that HSD-3.8 present in spermatocytes and sperm may participate in spermatogenesis and fertilization process by activating the PKC-dependent ERK1/2 signal transduction pathway.
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PMID:A sperm component, HSD-3.8 (SPAG1), interacts with G-protein beta 1 subunit and activates extracellular signal-regulated kinases (ERK). 1636 46

The asynchronous secretion of gonadotrope LH and FSH under the control of GnRH is crucial for ovarian cyclicity but the underlying mechanism is not fully resolved. Because prostaglandins (PG) are autocrine regulators in many tissues, we determined whether they have this role in gonadotropes. We first demonstrated that GnRH stimulates PG synthesis by induction of cyclooxygenase-2, via the protein kinase C/c-Src/phosphatidylinositol 3'-kinase/MAPK pathway in the LbetaT2 gonadotrope cell line. We then demonstrated that PGF(2alpha) and PGI2, but not PGE2 inhibited GnRH receptor expression by inhibition of phosphoinositide turnover. PGF(2alpha), but not PGI2 or PGE2, reduced GnRH-induction of LHbeta gene expression, but not the alpha-gonadotropin subunit or the FSHbeta subunit genes. The prostanoid receptors EP1, EP2, FP, and IP were expressed in rat gonadotropes. Incubations of rat pituitaries with PGF(2alpha), but not PGI2 or PGE2, inhibited GnRH-induced LH secretion, whereas the cyclooxygenase inhibitor, indomethacin, stimulated GnRH-induced LH secretion. None of these treatments had any effect on GnRH-induced FSH secretion. The findings have thus elaborated a novel GnRH signaling pathway mediated by PGF(2alpha)-FP and PGI2-IP, which acts through an autocrine/paracrine modality to limit autoregulation of the GnRH receptor and differentially inhibit LH and FSH release. These findings provide a mechanism for asynchronous LH and FSH secretions and suggest the use of combination therapies of GnRH and prostanoid analogs to treat infertility, diseases with unbalanced LH and FSH secretion and in hormone-dependent diseases such as prostatic cancer.
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PMID:Reciprocal cross talk between gonadotropin-releasing hormone (GnRH) and prostaglandin receptors regulates GnRH receptor expression and differential gonadotropin secretion. 1713 45

The relaxin family peptides, although structurally closely related to insulin, act on a group of four G protein-coupled receptors now known as Relaxin Family Peptide (RXFP) Receptors. The leucine-rich repeat containing RXFP1 and RXFP2 and the small peptide-like RXFP3 and RXFP4 are the physiological targets for relaxin, insulin-like (INSL) peptide 3, relaxin-3 and INSL5, respectively. RXFP1 and RXFP2 have at least two binding sites--a high-affinity site in the leucine-rich repeat region of the ectodomain and a lower-affinity site in an exoloop of the transmembrane region. Although they respond to peptides that are structurally similar, RXFP3 and RXFP4 demonstrate distinct binding properties with relaxin-3 being the only peptide that can recognize these receptors in addition to RXFP1. Activation of RXFP1 or RXFP2 causes increased cAMP and the initial response for both receptors is the resultant of Gs-mediated activation and G(oB)-mediated inhibition of adenylate cyclase. With RXFP1, an additional delayed increase in cAMP involves betagamma subunits released from G(i3). In contrast, RXFP3 and RXFP4 inhibit adenylate cyclase and RXFP3 causes ERK1/2 phosphorylation. Drugs acting at RXFP1 have potential for the treatment of diseases involving tissue fibrosis such as cardiac and renal failure, asthma and scleroderma and may also be useful to facilitate embryo implantation. Activators of RXFP2 may be useful to treat cryptorchidism and infertility and inhibitors have potential as contraceptives. Studies of the distribution and function of RXFP3 suggest that it is a potential target for anti-anxiety and anti-obesity drugs.
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PMID:Relaxin family peptide receptors--former orphans reunite with their parent ligands to activate multiple signalling pathways. 1729 90

Early mammalian embryogenesis is currently the focus of intense interest because of the potential of inner cell mass-derived embryonic stem cell lines in new therapeutic strategies. As such, creating molecular profiles of gene expression during pre-implantation development will provide a framework for understanding the biological properties of these cells and also establish a tool set for subsequent functional studies. However, a major obstacle impeding progress in this area are moral issues regarding their use, the scarcity of these cells and the ability to successfully isolate and amplify enough mRNA from the minute amounts of total RNA present in these cells. The elucidation, unravelling and understanding the molecular basis of transcriptional control during pre-implantation development is of utmost importance if we are to diagnose, intervene, eliminate or reduce abnormalities associated with growth, disease and infertility by applying assisted reproduction. Importantly, these studies should enhance our knowledge of basic reproductive biology and its application to regenerative medicine. This review describes the application of in silico-based approaches, in order to obtain maximal information from published microarray-based gene expression data. For an illustration of this, we used gene expression data related to unfertilized oocytes and blastocysts to gain insights into genes and related signalling pathways (e.g. MAPK, PI3K, WNT, TGF-beta) involved in the switch from maternal to embryonic control of gene transcription during human pre-implantation development.
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PMID:Functional genomics of human pre-implantation development. 1767 Jul 67

Millions of unnecessary cells are removed from our body everyday by apoptosis to ensure our survivals. Apoptosis is a highly coordinated process. Failure in apoptotic regulation results in disease. A large number of studies have demonstrated that accelerated apoptosis is involved in degenerative diseases, ischemic injuries, immunodeficiency and infertility. These studies have also revealed the molecular mechanisms of apoptosis signal transduction to provide therapeutic targets. On the other hand, protein transduction technology has been developed to deliver full-length proteins to various tissues including the brain. So far, many studies have shown that in vivo delivery of therapeutic proteins/peptides, including anti-apoptotic proteins, an anti-oxidant enzyme, a neuroprotectant, enzymes involved in purine or tyrosine metabolism, caspase inhibitors, c-Jun N-terminal kinase inhibitors and an NF-kappaB inhibitor, by protein transduction technology mitigates various diseases in animal models.
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PMID:PTD-mediated delivery of anti-cell death proteins/peptides and therapeutic enzymes. 1809 93

In Vitro maturation (IVM) of human oocytes is an emerging infertility treatment with great promise. To be successful this future assisted reproductive technology must entail both nuclear and cytoplasmic maturation of the oocytes and give rise to human embryos that have the same developmental potential as embryos resulting from the golden standard of human IVF. The aspiration of immature oocytes from small to medium size antral follicles followed by their maturation In Vitro present an attractive alternative to the hormonal stimulation of patients in In Vitro fertilization (IVF) treatment, since administration of exogenous hormones is a costly treatment and may cause severe health problems. Of the long list of side effect and health concern ovarian hyper-stimulation syndrome (OHSS) is by far the most severe although long term effect on cancer prevalence is another concern. Another potential group of patients that could benefit from future IVM treatments are the young women undergoing anticancer therapy (radiation- or chemotherapy). Thus, ovarian and oocyte cryopreservation techniques are emerging, however such treatments can only be fully realized when IVM becomes an efficient means of obtaining healthy birth. At present, the In Vitro maturation techniques are highly successful in mice, variable successful in domestic species and still regarded experimental in the human clinic due to suboptimal fertilization rates and embryo quality. This review discusses comparative studies of the processes of oocyte maturation In Vivo and In Vitro, in various mammalian species including human. Among the substances that have been reported to influence oocyte maturation there is an interesting endogenous signaling molecule: FF-MAS (4,4-dimethyl-5 alpha-cholest-8,14,24-trien-3 beta -ol), an intermediate in the cholesterol biosynthetic pathway present in all cells. This review gives special focus to FF-MAS, the effect seen in animal and human studies so far and its potential use in treatment of human infertility is being discussed, including both the safety and efficacy issues that need to be addressed. It is being reviewed how FF-MAS and related MAS analogues by our group and other scientific groups have been observed to mediate a dose-dependant response on both the nuclear maturation and especially the cytoplasmic maturation during oocyte maturation In Vitro thus giving rise to pre-embryos of higher developmental potential. Studies are reviewed regarding the family of meiosis activating sterols, its In Vivo regulation by gonadotropins (especially LH) and suggestions to the signaling pathways as the putative MAS receptor eliciting the important cytoplasmic maturation signaling cascade that involves mos/MAP kinase. The pharmacological effect of synthetic FF-MAS has been observed in various models and species, including murine, porcine and humane oocytes. Finally, the chromosome status of IVM human oocytes has been the focus of a large prospective clinical trial, documenting that FF-MAS acting on human oocytes during In Vitro maturation presents a safe procedure evaluated on numerical chromosome aberration rates in metaphase-II oocytes. In conclusion the In Vitro maturation of human oocytes is already now a valuable clinical treatment alternative for a subset of infertile patients, especially the Polycystic Ovarian Syndrome (PCOS) patients. IVM has the promise of being tomorrow's gold standard in treatment of human infertility if most of the important components of oocyte maturation are understood and can be adequately addressed In Vitro. Considering the present low frequency of successful fertilization and pre-implantation development following In Vitro maturation of human oocytes, the addition of FF-MAS or MAS analogues to the maturation medium to improve the cytoplasmic maturation and to yield higher quality pre-embryos may prove highly beneficial.
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PMID:Oocyte maturation. Basic and clinical aspects of in vitro maturation (IVM) with special emphasis of the role of FF-MAS. 1832 42


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