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)

Expression of vascular endothelial growth factor (VEGF) isoforms and its receptors, Flt-1 and KDR, was investigated during the period of peri-implantation in mink, a species that displays obligate embryonic diapause. Uterine samples were collected during diapause, embryo activation, and implantation from pseudopregnant and anestrous animals and analyzed by semiquantitative reverse transcription polymerase chain reaction and immunohistochemistry. The abundance of mRNA of VEGF isoforms 120, 164, and 188 was highest during late embryo activation and at implantation. VEGF protein was localized to the glandular epithelium at all stages of peri-implantation, whereas the luminal epithelium lacked VEGF reactivity during diapause. Endometrial stroma and luminal and glandular epithelia were positive for VEGF in implanted uteri. The invasive trophoblast cells of the implanting embryo were intensively stained. High levels of VEGF mRNA in pseudopregnant uteri indicates that VEGF upregulation leading to implantation is dependent upon maternal rather than embryonic factors. The abundance of the two receptors, KDR and Flt-1, increased in the uterus during implantation. Low levels of the receptors in pseudopregnant uteri compared with those containing activated or implanted embryos indicates that the embryo regulates receptor expression. These results demonstrate VEGF and VEGF receptor expression during early gestation in mink and suggest that maternal and embryonic input regulates different aspects of the angiogenic process.
...
PMID:Expression of vascular endothelial growth factor isoforms and receptors Flt-1 and KDR during the peri-implantation period in the mink, Mustela vison. 1260 84

c-kit is a proto-oncogene that codes for a transmembrane tyrosine kinase receptor (CD117). The gene product KIT is constitutively overexpressed in mastocytosis and gastrointestinal stromal tumors. Recently the use of the tyrosine kinase inhibitors, such as STI-571, has resulted in the successful treatment of bcr-abl-positive leukemias and gastrointestinal stromal tumors. In gastrointestinal stromal tumors, immunostaining for c-kit is diffusely positive. Because the expression of c-kit in mesenchymal tumors of the uterus and ovary has not been previously studied, we evaluated its expression in 38 of these tumors by immunohistochemistry. The number of positive labeled/total tumors were as follows: 0/8 malignant mullerian mixed tumors, 4/7 ovarian fibrosarcomas, 0/1 clear-cell ovarian sarcoma, 0/4 uterine leiomyosarcomas, 1/10 low-grade endometrial stromal sarcomas, 0/2 high-grade endometrial stromal sarcomas, and 3/6 endometrial stromal nodules. In all positive cases, no more than 5% of the cells were labeled. In conclusion, unlike gastrointestinal stromal tumors, mesenchymal tumors of the uterus and ovary rarely express c-kit. Therefore, it is unlikely that patients with these tumors will benefit from treatment with the currently available tyrosine kinase inhibitors.
...
PMID:Lack of expression of c-kit protein (CD117) in mesenchymal tumors of the uterus and ovary. 1264 74

It has been found that 4-estren-3alpha,17beta-diol, a synthetic ligand for the estrogen receptor (ER) or androgen receptor (AR), which does not affect classical transcription, reverses bone loss in ovariectomized females or orchidectomized males without affecting the uterus or seminal vesicles, demonstrating that the classical genotropic actions of sex steroid receptors are dispensable for their bone-protective effects, but indispensable for their effects on reproductive organs. We have now investigated the mechanism of action of this compound. We report that, identically to 17beta-estradiol or dihydrotestosterone, but differently from raloxifene, estren alters the activity of Elk-1, CCAAT enhancer binding protein-beta (C/EBPbeta), and cyclic adenosine monophosphate-response element binding protein (CREB), or c-Jun/c-Fos by an extranuclear action of the ER or AR, resulting in activation of the Src/Shc/ERK pathway or downregulation of JNK, respectively. All of these effects are non-sex specific, require only the ligand-binding domain of the receptor, and are indispensable for the antiapoptotic action of these ligands on osteoblastic and HeLa cells. Moreover, administration of 17beta-estradiol or 4-estren-3alpha,17beta-diol to ovariectomized mice induces phosphorylation of ERKs, Elk-1, and C/EBPbeta, downregulates c-Jun, and upregulates the expression of egr-1, an ERK/SRE target gene. Kinase-initiated regulation of commonly used transcription factors offers a molecular explanation for the profound skeletal effects of sex steroid receptor ligands, including synthetic ones that are devoid of classical transcriptional activity.
...
PMID:Kinase-mediated regulation of common transcription factors accounts for the bone-protective effects of sex steroids. 1278 64

The 3.8-kb full-length mouse Ptk7 cDNA encoding a defective receptor protein tyrosine kinase was cloned by reverse transcription-PCR of mouse liver mRNA. The mouse PTK7 polypeptide showed 92.6% identity to human PTK7. The mouse Ptk7 gene consists of 20 exons and has exactly the same exon structure as the human PTK7 gene. Mouse PTK7 was shown to be phosphorylated neither by itself nor by other protein tyrosine kinases. In addition, its expression did not affect the phospho-tyrosine level of cellular proteins in COS-1 cells. The mouse Ptk7 mRNA was expressed at high levels in lung and un-pregnant uterus among adult tissues, and in the tail, limbs, somites, gut, and craniofacial regions among embryonic tissues. These data suggest that mouse PTK7, an orthologue of human PTK7, plays multiple roles in embryonic development.
...
PMID:Cloning and characterization of the full-length mouse Ptk7 cDNA encoding a defective receptor protein tyrosine kinase. 1501 86

This is the first report in the English literature of a composite endometrial tumor composed of papillary serous carcinoma and small cell carcinoma. A 79-year-old woman underwent total abdominal hysterectomy and left salpingo-oophorectomy due to endometrial carcinoma. Grossly, the uterus was enlarged with an irregular and nodular serosal surface, thickened myometrium, and irregular endometrium. Microscopic examination revealed an endometrial carcinoma composed of papillary serous carcinoma and small cell carcinoma. There was a differential immunoreactivity between the two components: the cells of the papillary serous carcinoma were positive for cytokeratin, CA-125, CEA, and HER-2/Neu, whereas these markers were negative in the small cell carcinoma. Various neuroendocrine markers were positive in the small cell carcinoma and negative in the papillary serous carcinoma. Fluorescence in situ hybridization analysis using 4, 8, and 10 centromeric probes revealed hyperploidy (6-8 signals) in the small cell carcinoma cells. Most of the serous carcinoma cells were euploid, with scattered trisomies and tetrasomies of these chromosomes. The patient died of progressive disease 5 months after surgery. We suggest that the small cell carcinoma may have arisen from the endometrial papillary serous carcinoma undergoing tumor progression with neuroendocrine differentiation.
...
PMID:An unusual composite endometrial tumor combining papillary serous carcinoma and small cell carcinoma. 1525 20

Early growth response-1 (Egr-1) is an immediate-early gene induced by E2 in the rodent uterus and breast cancer cells. E2 induces Egr-1 mRNA and protein levels in MCF-7 human breast cancer cells and reporter gene activity in cells transfected with pEgr-1A, a construct containing the -600 to +12 region of the Egr-1 promoter linked to the firefly luciferase gene. Deletion analysis of the Egr-1 promoter identified a minimal E2-responsive region of the promoter that contained serum response element (SRE)3 (-376 to -350) which bound Elk-1 and serum response factor (SRF) in gel mobility shift assays. Hormone-responsiveness of Egr-1 in MCF-7 cells was specifically inhibited by PD98059, a mitogen-activated protein kinase kinase inhibitor, but not by LY294002, an inhibitor of phosphatidylinositol-3-kinase (PI3-K). These results contrasted with hormone-dependent activation of the SRE in the c-fos promoter, which was inhibited by both PD98059 and LY294002. Differences in activation of the SREs in Egr-1 and c-fos were related to promoter sequence, which defines the affinities of Elk-1 and SRF to their respective binding sites. Thus, Egr-1, like c-fos, is activated through non-genomic (extranuclear) pathways of estrogen action in breast cancer cells.
...
PMID:Egr-1 is activated by 17beta-estradiol in MCF-7 cells by mitogen-activated protein kinase-dependent phosphorylation of ELK-1. 1544 18

Within the reproductive system, oestrogenic stimulation of uterine and pituitary tissue typically causes a proliferative response accompanied by an angiogenic induction of new blood vessels from existing ones, thereby providing nutrients and oxygen to the growing tissue. The pro-oestrogenic pesticide methoxychlor (MXC), however, has shown a differential effect on proliferative activity. An increase in uterine growth is present, while the pituitary undergoes a decrease in size, even though the effect is accompanied by a characteristic oestrogen-induced elevation in pituitary prolactin concentration. The focus of the current study was whether the observed differences in tissue growth between uterus and pituitary in response to MXC administration were paralleled by a corresponding disparity in the expression of those growth factors (members of the vascular endothelial growth factor (VEGF) and angiopoietin families and their receptors) that are involved in the angiogenic cascade. Ovariectomized adult Sprague-Dawley female rats were administered MXC (0-200 mg/kg, oral) for 1 or 3 weeks. Immunohistochemical staining of uteri and pituitaries was performed under strictly controlled conditions for VEGF and its receptor VEGFR2, Angiopoietin-1 (Ang1) and angiopoietin-2 and their tyrosine kinase receptor Tie2, and platelet endothelial adhesion factor (as an index of vascularity). Image acquisition and densitometric assessments of staining intensity were conducted under blind conditions. The results showed uterine MXC-induced increases in the expression of VEGFR2 and Ang1, changes consistent with a normal proliferative response to oestrogenic stimulation. For VEGF, staining tended to be most pronounced in the stromal region, although there did not appear to be a progressive increase with dose. VEGFR2 expression showed significant dose-related trends in luminal and glandular epithelia by 1 week. Similar effects at 1 week were evident for Ang1 in glandular epithelium. In the anterior pituitary, a dose-related increase in VEGF was present for the 1 and 3 week treatments, and the number of pituitary vessels per unit area was also increased after 3 weeks. The effects indicate that even though the insecticide has not been found to cause an augmentation in pituitary growth, a dose-related rise in the expression of at least one principal angiogenic factor is present that may be associated with an increase in vascular density.
...
PMID:Methoxychlor-induced alterations in the histological expression of angiogenic factors in pituitary and uterus. 1550 10

Blastocyst implantation is a critical process in the establishment of pregnancy in eutherian mammals and requires a harmonious symbiosis between the developing conceptus and the differentiating maternal uterus. A better understanding of this symbiotic relationship will provide novel approaches and interventions for realizing anti-implantation strategies for effective fertility regulation and reproductive health care management. We have been using the rhesus monkey (Macaca mulatta) as a nonhuman primate model to this end. In the present study, the process of progesterone-mediated regulation of endometrial receptivity for blastocyst implantation has been targeted by the use of mifepristone as an emergency contraceptive agent. Furthermore, based on cell-specific, temporal and spatial distribution of vasotropic cytokines and mediators in the "receptive" and periimplantation periods, the pregnancy interceptive potentials of (a) monoclonal antibody (MAb) to leukemia inhibitory factor (LIF); (b) inhibitors of nitric oxide synthase [e.g., N6-nitro-l-arginine (l-NAME) and aminoguanidine]; and (c) MAb to vascular endothelial growth factor (VEGF) were examined. LIF is a progesterone-responsive pleiotropic cytokine that functions as a proinflammatory cytokine, together with interleukins 1 and 6, during the process of implantation-placentation in primates, and its immunoneutralization with MAb resulted in inhibition (p<.04) of pregnancy establishment in the rhesus monkey. However, timed administration of l-NAME or aminoguanidine failed to inhibit blastocyst implantation in a significant manner. Also, no synergistic antinidatory action of antiprogestin combined with l-NAME was detected in the rhesus monkey. The application of MAb to VEGF during the periimplantation period, on the other hand, led to significant (p<.04) prevention of pregnancy without influencing steroid hormone levels in the circulation. Our data lend support to the hypothesis that VEGF is essential for pregnancy establishment and that trophoblast-derived VEGF, acting via its specific receptors Flt-1 and KDR, is necessary for blastocyst implantation. The use of cDNA-based expression arrays followed by differential display analysis has provided preliminary understanding of the nature of gene cluster networks operative in the receptive endometrium of potential conception cycles in the rhesus monkey. This knowledge may, in the future, lead to further innovative anti-implantation strategies for targeted pregnancy interception.
...
PMID:Target-oriented anti-implantation approaches for pregnancy interception: experiences in the rhesus monkey model. 1579 48

The brain of both sexes is a major target of estradiol and a site of estrogen synthesis during development and in the adult. In addition to the classical intranuclear estrogen receptors (ERs) ER-alpha and ER-beta, we have recently identified a novel, plasma membrane-associated ER that is neither ER-alpha nor ER-beta in the brain and uterus, which we have designated "ER-X". ER-X is a developmentally regulated estrogen-binding protein that is present in wild-type, ER-alpha gene-disrupted (alphaERKO) and ER-alpha-null mice. ER-X is re-expressed after ischemic brain injury and in adult transgenic mice with Alzheimer's disease. Although ER-X shares some homology with the C-terminal region of ER-alpha, it is not an alternative splicing variant of ER-alpha and may be a new gene. ER-X mediates 17alpha-estradiol and 17beta-estradiol activation of MAPK/ERK. In contrast, ER-alpha does not elicit ERK activation but, surprisingly, is inhibitory. The potential importance of 17alpha-estradiol, the preferred ligand of ER-X, for the brain is underscored by our findings by liquid chromatography/tandem mass spectrometry that the endogenous levels of 17alpha-estradiol are significantly elevated in the postnatal day-7 and adult mouse neocortex and hippocampus, as compared with 17beta-estradiol. That there is so much more 17alpha-estradiol than 17beta-estradiol in the brain suggests that this enantiomer would be readily available to the brain. In considering estrogens for postmenopausal treatment, one should consider all the ERs present in the brain, not just ER-alpha and ER-beta, but ER-X as well, and focus on ligands such as 17alpha-estradiol that may be more selective for this ER.
...
PMID:Estrogen and the brain: beyond ER-alpha, ER-beta, and 17beta-estradiol. 1602 56

In humans, fetal cytotrophoblasts leave the placenta and enter the uterine wall, where they preferentially remodel arterioles. The fundamental mechanisms that govern these processes are largely unknown. Previously, we have shown that invasive cytotrophoblasts express several chemokines, as well as the receptors with which they interact. Here, we report that these ligand-receptor interactions stimulate cytotrophoblast migration to approximately the same level as a growth factor cocktail that includes serum. Additionally, cytotrophoblast commitment to uterine invasion was accompanied by rapid downregulation of EPHB4, a transmembrane receptor associated with venous identity, and upregulation of ephrin B1. Within the uterine wall, the cells also upregulated expression of ephrin B2, an EPH transmembrane ligand that is associated with arterial identity. In vitro cytotrophoblasts avoided EPHB4-coated substrates; upon co-culture with 3T3 cells expressing this molecule, their migration was significantly inhibited. As to the mechanisms involved, cytotrophoblast interactions with EPHB4 downregulated chemokine-induced but not growth factor-stimulated migration. We propose that EPHB4/ephrin B1 interactions generate repulsive signals that direct cytotrophoblast invasion toward the uterus, where chemokines stimulate cytotrophoblast migration through the decidua. When cytotrophoblasts encounter EPHB4 expressed by venous endothelium, ephrin B-generated repulsive signals and a reduction in chemokine-mediated responses limit their interaction with veins. When they encounter ephrin B2 ligands expressed in uterine arterioles, migration is permitted. The net effect is preferential cytotrophoblast remodeling of arterioles, a hallmark of human placentation.
...
PMID:EPHB4 regulates chemokine-evoked trophoblast responses: a mechanism for incorporating the human placenta into the maternal circulation. 1610 76


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

---