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

---

Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Secretion of gonadotropin-releasing hormone (GnRH) at the median eminence is the essential activator of the reproductive axis. The mechanisms by which embryonic GnRH neurons migrate from the olfactory placode to the preoptic area and then elaborate neurites that course through the hypothalamus to terminate at the median eminence are largely unknown. We investigated the hypothesis that GnRH neurite outgrowth is promoted by brain-derived neurotrophic factor (BDNF) because GnRH neurites course through BDNF-rich areas of the forebrain during their development. Confocal microscopy revealed that most (86%) cultured embryonic GnRH cells tagged with a green fluorescent protein reporter were immunoreactive for TrkB. In primary cultures of E12.5 olfactory tissue, treatment with BDNF induced a dose-dependent increase in neurite outgrowth, but had no discernible effect on branching. BDNF induced phosphorylation of Ca(2+)/cAMP response element-binding protein (pCREB) in both GnRH and non-GnRH cells in these cultures. This was not associated with phosphorylation of ERK in GnRH-immunoreactive cells, though BDNF treatment did stimulate pERK in neighbouring non-GnRH cells. Promotion of neurite outgrowth is unlikely therefore to result from activation of the Ras-MAPK/ERK pathway. We conclude that the developing GnRH secretory system is directly sensitive to BDNF and that this polypeptide functions as a neurotrophic factor for GnRH neurons.
...
PMID:Neurotrophic effects of BDNF on embryonic gonadotropin-releasing hormone (GnRH) neurons. 1523 43

Glial erbB-1 and erbB-4 receptors are key components of the process by which neuroendocrine glial cells control LHRH secretion and the onset of female puberty. We now provide evidence that these two signaling systems work in a coordinated fashion to control reproductive function. To generate animals carrying functionally impaired erbB-1 and erbB-4 receptors, we crossed Waved 2 (Wa-2+/+) mice harboring a point mutation of the erbB-1 receptor with mice expressing a dominant-negative erbB-4 receptor in astrocytes. In comparison to single-deficient mice, double-mutant animals exhibited a further delay in the onset of puberty and a strikingly diminished adult reproductive capacity. Ligand-dependent erbB receptor phosphorylation and erbB-mediated MAPK (ERK 1/2) phosphorylation were impaired in mutant astrocytes. Wa-2+/+ or double-mutant astrocytes failed to respond to TGF alpha with production of prostaglandin E2, one of the factors mediating the stimulatory effect of astroglial erbB receptor activation on LHRH release. Medium conditioned by Wa-2+/+ or double-mutant astrocytes treated with TGF alpha failed to stimulate LHRH release from GT1-7 cells. The LH response to ovariectomy was significantly attenuated in mutant mice in comparison with wild-type controls. Although the Wa-2 mutation affects all cells bearing erbB-1 receptors, these results suggest that a major defect underlying the reproductive defects of animals with impaired erbB signaling is a decreased ability of glial cells to stimulate LHRH release. Thus, a coordinated involvement of erbB-1 and erbB-4 signaling systems is required for the normalcy of sexual development and the maintenance of mature female reproductive function.
...
PMID:erbB-1 and erbB-4 receptors act in concert to facilitate female sexual development and mature reproductive function. 1559 Nov 45

Although a novel second form of GnRH (GnRH-II) has been reported to have an antiproliferative effect on gynecologic cancer cells, its biological mechanism remains to be elucidated. We have previously demonstrated that GnRH-II activates p38 MAPK. There is accumulating evidence that activation of MAPKs by GnRH-I and -II is important for cell proliferation, differentiation, and apoptosis. In the present study, we further investigated the involvement of GnRH-II in the inhibition of cell proliferation and activation of ERK1/2 and c-Jun N-terminal protein kinase/stress-activated protein kinase (JNK/SAPK) in ovarian cancer cells, OVCAR-3. The [(3)H]thymidine incorporation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that treatment with GnRH-II suppresses cell proliferation of ovarian cancer cells. Western blot analysis demonstrated that ERK1/2 was activated by GnRH-II (100 nm). Moreover, PD98059 (10 mum), an inhibitor of a MAPK/ERK kinase, reversed the activation of ERK1/2 induced by GnRH-II. The activation of ERK1/2 by GnRH-II subsequently phosphorylated Elk-1 as a downstream pathway, which was blocked by PD98059. On the other hand, it is not likely that GnRH-II activates the JNK/SAPK pathway. Taken together, these results indicate that the ERK1/2 pathway is involved in the effect of GnRH-II on antiproliferation and may be an important target for ovarian cancer therapy.
...
PMID:Extracellular signal-regulated protein kinase, but not c-Jun N-terminal kinase, is activated by type II gonadotropin-releasing hormone involved in the inhibition of ovarian cancer cell proliferation. 1559 81

Type I gonadotropin-releasing hormone (GnRH) receptor (GnRHR) is unique among mammalian G-protein-coupled receptors (GPCRs) in lacking a C-terminal tail, which is involved in desensitization in GPCRs. Therefore, we searched for inhibitory sites in the intracellular loops (ICLs) of the GnRHR. Synthetic peptides corresponding to the three ICLs were inserted into permeabilized alphaT3-1 gonadotrope cells, and GnRH-induced inositol phosphate (InsP) formation was determined. GnRH-induced InsP production was potentiated by ICL2 > ICL3 but not by the ICL1 peptides, suggesting they are acting as decoy peptides. We examined the effects of six peptides in which only one of the Ser or Thr residues was substituted with Ala or Glu. Only substitution of Ser153 with Ala or Glu ablated the potentiating effect upon GnRH-induced InsP elevation. ERK activation was enhanced, and the rate of GnRH-induced InsP formation was about 6.5-fold higher in the first 10 min in COS-1 cells that were transfected with mutants of the GnRHR in which the ICL2 Ser/Thr residues (Ser151, Ser153, and Thr142) or only Ser153 was mutated to Ala as compared with the wild type GnRHR. The data indicate that ICL2 harbors an inhibitory domain, such that exogenous ICL2 peptide serves as a decoy for the inhibitory site (Ser153) of the GnRHR, thus enabling further activation. GnRH does not induce receptor phosphorylation in alphaT3-1 cells. Because the phosphomimetic ICL2-S153E peptide did not mimic the stimulatory effect of the ICL2 peptide, the inhibitory effect of Ser153 operates through a phosphorylation-independent mechanism.
...
PMID:Identification of Ser153 in ICL2 of the gonadotropin-releasing hormone (GnRH) receptor as a phosphorylation-independent site for inhibition of Gq coupling. 1596 50

Luteinizing hormone and gonadotropin releasing hormone receptors (LHR and GnRHR, respectively) are G protein-coupled receptors with important functions in reproduction. We have developed chimeric GnRHR-LHR that contain the full GnRHR coupled to various forms of the LH receptor C-terminus to explore the role of the LH receptor C-terminus in raft localization of the receptor and signaling. Addition of the full-length LHR C-terminus to GnRHR resulted in localization of the resting chimeric receptor in the bulk membrane rather than plasma membrane rafts as has been reported for the wild-type GnRHR [A. Navratil, S. Bliss, K. Berghorn, J. Haughian, T. Farmerie, J. Graham, C. Clay, M. Roberson, Constitutive localization of the gonadotropin-releasing hormone (GnRH) receptor to low density membrane microdomains is necessary for GnRH signaling to ERK, J. Biol. Chem. 278 (2003) 31593-31602]. With truncation of the LHR C-terminus, approximately 3% of chimeric receptors appeared in low density membrane fractions. Palmitoylation of sites on the LHR C-terminus appears important for raft localization. Mutations to C-terminus palmitoylation sites eliminated translocation of LH receptors from the bulk membrane to rafts upon binding of hCG although these mutant receptors retained the ability to signal via cAMP.
...
PMID:Chimeric GnRH-LH receptors and LH receptors lacking C-terminus palmitoylation sites do not localize to plasma membrane rafts. 1620 72

There is now compelling evidence that both normal puberty and disturbed pubertal development of central origin are, to a significant extent, determined by genetic factors. Although delayed sexual development can result from a deficient pituitary responsiveness to GnRH caused by mutations in the GnRH receptor gene, until recently the only genetically determined hypothalamic defects known to affect puberty were those caused by mutations in genes required for the migration of gonadotropin releasing hormone (GnRH) neurons, such as KAL1, FGFR1, and NELF. Recently, mutations in a gene termed GPR54 were identified as causing isolated hypogonadotrophic hypogonadism (IHH), due to a functional, instead of a structural hypothalamic defect. Studies in nonhuman primates and rodent models suggest that the functional integrity of the hypothalamic mechanism controlling puberty requires a gene network that includes GPR54. Altogether, these findings indicate that the genetic underpinnings of disturbed pubertal development of central origin are polygenic, rather than specified by a single gene.
...
PMID:Genes involved in the neuroendocrine control of normal puberty and abnormal puberty of central origin. 1636 80

The introduction of third generation aromatase inhibitors [anastrozole, letrozole, and exemestane] has certainly improved outcomes inpatients with early breast cancer. Although survival benefit has not been identified (except in the subpopulation of patients with lymph node positive breast cancer on the MA 17 study), the primary endpoints in all studies reached statistical significance in favor of AI. The strategy can include: replacing TAM outright after diagnosis; switching from TAM to one of the aromatase inhibitors after 2-3 years; or to add an AI after 5 years of TAM. DFS, recurrence, and the incidence of contra lateral breast cancer is influenced favorably with such an approach. The following issues remained unanswered: Will the OS be improved as well? Is the incidence of serious long-term side effects acceptable to our patients [osteoporosis, fractures, cognitive function and lipid profile changes]? What is the influence of chemotherapy on the effect of aromatase inhibitors? We still do not know the true role of AI in HER2 positive disease. Which effect do AI have in pre-menopausal women(with the use of LHRH agonists)? How long should patients after TAM be receiving AI? Several of these questions will be certainly answered with the new generation of studies, but many of these questions have just been generated with these new results.
...
PMID:Changing the gold standard in adjuvant therapy for breast cancer:from tamoxifen to aromatase inhibition. 1652 2

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome.
...
PMID:Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. 1705 99

An up-to-date review of the genetic aspects of idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS) is presented. Because proper development of the neuroendocrine axis must occur for normal puberty and reproductive function, gonadotropin-releasing hormone (GnRH) neuron migration is outlined first, followed by an introduction to the in vitro analysis of GnRH neuron migration. The normal hypothalamic-pituitary-gonadal (HPG) axis at different ages is discussed, along with a brief overview of normal and delayed puberty in both boys and girls. The phenotype of IHH/KS is discussed in detail, with its relation to Mendelian inheritance and chromosomal translocations. The molecular basis of IHH/KS is reviewed, with particular emphasis on the three most common genes ( KAL1, FGFR1, and GNRHR) that possess mutations in these patients. However, all other known genes for which mutations occur are also addressed briefly. The goal of this review is to provide a comprehensive discussion of IHH/KS, and to include both basic science and clinical findings that should allow a more complete understanding of hypothalamic-pituitary neuroendocrinology that is important in puberty and reproduction.
...
PMID:The genetics of hypogonadotropic hypogonadism. 1759 8

An adequate vascular supply is important to provide endocrine and paracrine signals during follicular development. We evaluated the direct in vivo effects of both the GnRH-agonist Leuprolide acetate (LA) and the GnRH-antagonist Antide (Ant) on the expression of VEGF-A and ANPT-1 and their receptors in ovarian follicles from prepubertal eCG-treated rats. We also examined whether the changes observed in apoptosis by GnRH-I analogs have an effect on the caspase cascade. LA significantly decreased the levels of VEGF-A, its receptor Flk-1, and ANPT-1 when compared to controls, while the co-injection of Ant interfered with this effect. No changes were observed in the levels of Tie-2 after treatment with these analogs. When we measured the follicular content of caspase-3 protein, we observed that LA significantly increased the level of the active form. The co-injection of Ant interfered with this effect and Ant alone significantly decreased caspase-3 cleavage. IHC analyses corroborated these data. Notably, while LA increased caspase-3 activity levels, Ant decreased them when compared to controls. In follicles obtained from LA-treated rats, cleavage of PARP (a substrate of caspase-3) from the intact 113-kDa protein showed a significant enhancement in an 85-kDa fragment. The co-injection of Ant interfered with this effect. Ant alone significantly decreased PARP cleavage as compared to controls. We conclude that the decrease in VEGF-A, its receptor Flk-1/KDR, and ANPT-1 produced by the administration of GnRH-I agonist is one of the mechanisms involved in ovarian cell apoptosis. This suggests an intraovarian role of an endogenous GnRH-like peptide in gonadotropin-induced follicular development.
...
PMID:Regulation of ovarian angiogenesis and apoptosis by GnRH-I analogs. 1787 66


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---