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Pathways Important (pathway + important)
Kinds of Pathways Important Selected AbstractsRegulation of Human Myometrial Contractility During Pregnancy and Labour: Are Calcium Homeostatic Pathways Important?EXPERIMENTAL PHYSIOLOGY, Issue 2 2001Rachel M. Tribe If we are to develop new strategies for the treatment and management of preterm and dysfunctional term labour, it is imperative that we improve current understanding of the control of human uterine activity. Despite many studies of animal pregnancy, there is a paucity of knowledge relating to the complex control of human myometrium during pregnancy. It is hypothesized that human myometrium is relatively quiescent during the majority of pregnancy and that as term approaches there is cascade of molecular events that prepare the uterus for labour. This review will consider the cellular mechanisms involved in the regulation of human myometrial activity and the modulation of these by hormonal and mechanical signals. In particular, the contribution of calcium homeostatic pathways to the control of human myometrial contractility during gestation will be discussed. [source] PTEN, Akt, and GSK3, signalling in rat primary cortical neuronal cultures following tumor necrosis factor-, and trans-4-hydroxy-2-nonenal treatmentsJOURNAL OF NEUROSCIENCE RESEARCH, Issue 3 2006A. Rickle Abstract PTEN is a dual phosphatase that negatively regulates the phosphatidylinositol 3-kinase (PI3K)/Akt signalling pathway important for cell survival. We determined effects of the inflammation and oxidative stresses of tumor necrosis factor-, (TNF,) and trans-4-hydroxy-2-nonenal (HNE), respectively, on PTEN, Akt, and GSK3, signalling in rat primary cortical neurons. The inhibitors bisperoxovanadium [bpV(Pic)] and LY294002 were also used to determine PTEN and PI3K involvement in TNF, and HNE modulation of neuronal cell death. PTEN inhibition with bpV(Pic) alone did not affect Ser473Akt or Ser9GSK3, phosphorylation. Instead, effects of this inhibitor were manifest when it was used together with TNF, and to a lesser extent with HNE. TNF, together with PTEN inhibition increased phosphorylation of Ser473Akt and Ser9GSK3,. TNF, and HNE both gave decreased numbers of viable and increased numbers of early apoptotic neurons. PTEN inhibition partially reversed the toxic effect of TNF, as shown by an increased number of viable and a decreased number of early apoptotic neurons. All effects were reversed by PI3K inhibition. HNE together with inhibition of PTEN gave increased Ser473Akt but not Ser9GSK3, phosphorylation and no effects on the number of viable or early apoptotic cells. In conclusion, PTEN inhibition gives a mild reversal of TNF,- but not HNE-induced cell death via the PI3K pathway. © 2006 Wiley-Liss, Inc. [source] Accentuated Ovariectomy-Induced Bone Loss and Altered Osteogenesis in Heterozygous N-Cadherin Null Mice,,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2006Chung Fang Lai Abstract Ovariectomy-induced bone loss is accentuated in mice with germline Cdh2 haploinsufficiency, the result of a decreased osteoblastogenesis in the face of normal osteoclast number. Reduced N-cadherin abundance in these mice decreases cell,cell adhesion and alters signaling pathways important for osteoblast commitment and differentiation, thus providing in vivo evidence that N-cadherin,mediated cell,cell interactions are involved in homeostatic responses to increased bone remodeling. Introduction: We have shown that targeted expression of a dominant negative truncated form of N-cadherin (Cdh2) delays acquisition of peak bone mass in mice and retards osteoblast differentiation. We tested the role of this molecule in the skeletal homeostatic response to ovariectomy in mice with germline Cdh2 haploinsufficiency. Materials and Methods: Heterozygous Cdh2 null (Cdh2+/,) and wildtype mice were ovariectomized and followed up to 13 weeks by in vivo radiodensitometric and ex vivo histologic assessment of bone mass and turnover. Cells isolated from wildtype and Cdh2+/, mice were used to determine the alterations in bone cell function produced by partial loss of N-cadherin. Results: Bone mass was not significantly different between Cdh2+/, and wildtype littermates, but on ovariectomy, bone loss in Cdh2+/, mice was initially slower, but with time it became significantly greater than in wildtype mice. This accentuated bone loss was associated with lower osteoblast number and serum osteocalcin levels, with no differences in bone resorption. Although development of calcified nodules was faster in calvaria cells isolated from Cdh2+/, mice relative to Cdh2+/+ cells, bone marrow osteogenic precursors were lower in the former than in the latter genotypes. Cdh2 expression was downregulated with differentiation in wildtype calvaria cells, whereas cadherin-11 abundance remained unchanged. Furthermore, cell,cell adhesion (postconfluence) was decreased among heterozygous calvaria cells, as was cell proliferation (preconfluence), relative to wildtype cells. Finally, the abundance and cellular distribution of ,-catenin was minimally decreased in Cdh2+/, cells, whereas mitogen-activated protein kinase (MAPK) signaling was more active in Cdh2 insufficient cells. Conclusions:Cdh2 is involved in the homeostatic bone formation response to ovariectomy, presumably by regulating osteoprogenitors number and differentiation through stabilization of cell,cell adhesion and/or signaling modulation. [source] All in the family: Using inherited cancer syndromes to understand de-regulated cell signaling in brain tumorsJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2007S. Sean Houshmandi Abstract The cell signaling pathways that are tightly regulated during development are often co-opted by cancer cells to allow them to escape from the constraints that normally limit cell growth and cell movement. In this regard, de-regulated signaling in cancer cells confers a number of key tumor-associated properties, including increased cell proliferation, decreased cell death, and increased cell motility. The identification of some of these critical signaling pathways in the nervous system has come from studies of inherited cancer syndromes in which affected individuals develop brain tumors. The study of brain tumors arising in patients with neurofibromatosis 1 (NF1), neurofibromatosis 2 (NF2), and tuberous sclerosis complex (TSC) has already uncovered several key intracellular signaling pathways important for modulating brain tumor growth. An in-depth analysis of these intracellular signaling pathways will not only lead to an improved understanding of the process of brain tumorigenesis, but may also provide important molecular targets for future therapeutic drug design. J. Cell. Biochem. 102: 811,819, 2007. © 2007 Wiley-Liss, Inc. [source] Molecular characterization of protein kinase C-, binding to lamin AJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 2 2002Alberto M. Martelli Abstract Previous results from our laboratory have identified lamin A as a protein kinase C (PKC)-binding protein. Here, we have identified the regions of PKC-, that are crucial for this binding. By means of overlay assays and fusion proteins made of glutathione-S-transferase (GST) fused to elements of rat PKC-,, we have established that binding occurs through both the V5 region and a portion of the C2 region (i.e., the calcium-dependent lipid binding (CaLB) domain) of the kinase. In particular, we have found that amino acid 200,217 of the CaLB domain are essential for binding lamin A, as a synthetic peptide corresponding to this stretch of amino acids prevented the interaction between the CaLB domain and lamin A. We also show that the presence of four lysine residues of the CaLB domain (K205, K209, K211, and K213) was essential for the binding. We have determined that binding of elements of PKC-, to lamin A does not require the presence of cofactors such as phosphatidylserine (PS) and Ca2+. We have also found that the binding site of lamin A for the CaLB domain of PKC-, is localized in the carboxyl-terminus of the lamin, downstream of amino acid 499. Our findings may prove to be important to clarify the mechanisms regulating PKC function within the nucleus and may also lead to the synthesis of isozyme-specific drugs to attenuate or reverse PKC-dependent nuclear signaling pathways important for the pathogenesis of cancer. © 2002 Wiley-Liss, Inc. [source] Shuttle craft: a candidate quantitative trait gene for Drosophila lifespanAGING CELL, Issue 5 2004Elena G. Pasyukova Summary Variation in longevity in natural populations is attributable to the segregation of multiple interacting loci, whose effects are sensitive to the environment. Although there has been considerable recent progress towards understanding the environmental factors and genetic pathways that regulate lifespan, little is known about the genes causing naturally occurring variation in longevity. Previously, we used deficiency complementation mapping to map two closely linked quantitative trait loci (QTL) causing female-specific variation in longevity between the Oregon (Ore) and 2b strains of Drosophila melanogaster to 35B9,C3 and 35C3 on the second chromosome. The 35B9,C3 QTL encompasses a 50-kb region including four genes, for one of which, shuttle craft (stc), mutations have been generated. The 35C3 QTL localizes to a 200-kb interval with 15 genes, including three genes for which mutations exist (reduced (rd), guftagu (gft) and ms(2)35Ci). Here, we report quantitative complementation tests to mutations at these four positional candidate genes, and show that ms(2)35Ci and stc are novel candidate quantitative trait genes affecting variation in Drosophila longevity. Complementation tests with stc alleles reveal sex- and allele-specific failure to complement, and complementation effects are dependent on the genetic background, indicating considerable epistasis for lifespan. In addition, a homozygous viable stc allele has a sex-specific effect on lifespan. stc encodes an RNA polymerase II transcription factor, and is an attractive candidate gene for the regulation of longevity and variation in longevity, because it is required for motoneuron development and is expressed throughout development. Quantitative genetic analysis of naturally occurring variants with subtle effects on lifespan can identify novel candidate genes and pathways important in the regulation of longevity. [source] Young, adult, and old rats have similar changes in mRNA expression of many skeletal genes after fracture despite delayed healing with ageJOURNAL OF ORTHOPAEDIC RESEARCH, Issue 10 2006Ralph A. Meyer Jr. Abstract Genes active in fracture healing are not well understood. Because age slows skeletal repair, the change in gene expression between animals of differing ages may illuminate novel pathways important to this healing response. To explore this, 6-, 26-, and 52-week-old female Sprague-Dawley rats were subjected to mid-diaphyseal femoral fracture with intramedullary fixation. The fracture callus was collected at 0, 0.4 (3 days), 1, 2, 4, or 6 weeks after fracture. RNA was extracted and pooled between two animals for each sample. Three samples were done for each time point for each age for a total of 54 Affymetrix U34A GeneChip microarrays. Of the 8700 genes on each array, 3300 were scored as present. Almost all of these genes were affected by femoral fracture with either upregulation or downregulation in the 6 weeks after fracture. Upregulated genes included markers for matrix genes for both cartilage and bone, osteoblasts, osteocytes, osteoclasts, fibroblasts, and mast cells. Downregulated genes included genes related to blood cell synthesis. Nearly all genes presently associated with bone metabolism showed the same response to fracture healing regardless of the age of the animal. In conclusion, skeletal fracture led to similar changes in RNA expression for most skeletal genes despite the delay in the formation of bone to bridge the fracture gap in old rats. Defects in the healing of skeletal trauma in older rats may lie in systems not normally studied by skeletal biologists. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 24:1933,1944, 2006 [source] Characterization of the 3p12.3-pcen region associated with tumor suppression in a novel ovarian cancer cell line model genetically modified by chromosome 3 fragment transferMOLECULAR CARCINOGENESIS, Issue 12 2009Neal A.L. Cody Abstract The genetic analysis of nontumorigenic radiation hybrids generated by transfer of chromosome 3 fragments into the tumorigenic OV-90 ovarian cancer cell line identified the 3p12.3-pcen region as a candidate tumor suppressor gene (TSG) locus. In the present study, polymorphic microsatellite repeat analysis of the hybrids further defined the 3p12.3-pcen interval to a 16.1 Mb common region containing 12 known or hypothetical genes: 3ptel - ROBO2-ROBO1-GBE1-CADM2-VGLL3-CHMP2B-POU1F1-HTR1F-CGGBP1-ZNF654-C3orf38-EPHA3 -3pcen. Seven of these genes, ROBO1, GBE1, VGLL3, CHMP2B, CGGBP1, ZNF654, and C3orf38, exhibited gene expression in the hybrids, placing them as top TSG candidates for further analysis. The expression of all but one (VGLL3) of these genes was also detected in the parental OV-90 cell line. Mutations were not identified in a comparative sequence analysis of the predicted protein coding regions of these candidates in OV-90 and donor normal chromosome 3 contig. However, the nondeleterious sequence variants identified in the transcribed regions distinguished parent of origin alleles for ROBO1, VGLL3, CHMP2B, and CGGBP1 and cDNA sequencing of the hybrids revealed biallelic expression of these genes. Interestingly, underexpression of VGLL3 and ZNF654 were observed in malignant ovarian tumor samples as compared with primary cultures of normal ovarian surface epithelial cells or benign ovarian tumors, and this occurred regardless of allelic content of 3p12.3-pcen. The results taken together suggest that dysregulation of VGLL3 and/or ZNF654 expression may have affected pathways important in ovarian tumorigenesis which was offset by the transfer of chromosome 3 fragments in OV-90, a cell line hemizygous for 3p. Mol. Carcinog. © 2009 Wiley-Liss, Inc. [source] The role of the RNA-binding protein Sam68 in mammary tumourigenesis,THE JOURNAL OF PATHOLOGY, Issue 3 2010David J Elliott Abstract The RNA binding protein Sam68 (Src- associated in mitosis 68 kD) is implicated in cell signalling, transcriptional regulation, pre-mRNA splicing, and is overexpressed and/or hyperphosphorylated in breast, prostate, and renal cancers. Sam68 has roles in normal breast development; however, a study by Song et al published in this issue of The Journal of Pathology reports overexpression of nuclear and cytoplasmic Sam68 protein in a large cohort of clinical breast tumours, implicating Sam68 as a potential prognostic indicator and target for therapy. In breast cancer cells, nuclear Sam68 protein might affect the expression of cancer-relevant genes and/or modulate exon splicing patterns in a dose-dependent manner. Sam68-regulated expression of alternative transcripts may help drive mammary tumourigenesis. The high levels of cytoplasmic Sam68 protein observed in breast cancer cells could also impact on cellular signalling pathways important for mammary tumour cell biology. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Invited Commentary for Song L et al. Sam68 up-regulation correlates with, and its down-regulation inhibits, proliferation and tumourigenicity of breast cancer cells. Journal of Pathology, http://dx.doi.org/10.1002/path.2751 [source] Erythropoietin Receptor Is Expressed on Human Peripheral Blood T and B Lymphocytes and Monocytes and Is Modulated by Recombinant Human Erythropoietin TreatmentARTIFICIAL ORGANS, Issue 8 2010Katarzyna A. Lisowska Abstract Erythropoietin receptor (EPO-R) appears on the cell surface in the early stages of erythropoiesis. It has also been found on endothelial cells and polymorphonuclear leukocytes, suggesting erythropoietin (EPO) role beyond erythropoiesis itself. Earlier reports have shown that treatment with recombinant human erythropoietin (rhEPO) in chronic renal failure (CRF) patients improves interleukin-2 production and restores the T lymphocyte function. We decided to investigate possible expression of EPO-R on circulating peripheral blood lymphocytes and monocytes of CRF patients in order to assess the possibility of rhEPO direct action on these cells. Flow cytometry was used for detection and quantification of EPO-R, and reverse transcription polymerase chain reaction for detection of the EPO receptor mRNA. Our results show for the first time the existence of EPO-R on cell surface of human T and B lymphocytes and monocytes as well as at the transcriptional activity of the EPO-R gene in these cells, both in healthy and CRF individuals. We have also found significant differences between the numbers of EPO-R molecules on T and B lymphocytes of CRF patients not treated and treated with rhEPO and healthy control. Discovery of EPO-R expression on human lymphocytes suggests that EPO is probably able to directly modulate some signaling pathways important for these cells. [source] | |||||||||||||