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Divergent Regulation (divergent + regulation)

Distribution by Scientific Domains

Medical Sciences	60%

Selected Abstracts

Basic Fibroblast Growth Factor Stimulates Vascular Endothelial Growth Factor Release in Osteoblasts: Divergent Regulation by p42/p44 Mitogen-Activated Protein Kinase and p38 Mitogen-Activated Protein Kinase

JOURNAL OF BONE AND MINERAL RESEARCH, Issue 12 2000
Haruhiko Tokuda
Abstract We previously showed that basic fibroblast growth factor (bFGF) activates p38 mitogen-activated protein (MAP) kinase via Ca2+ mobilization, resulting in interleukin-6 (IL-6) synthesis in osteoblast-like MC3T3-E1 cells. In the present study, we investigated the effect of bFGF on the release of vascular endothelial growth factor (VEGF) in these cells. bFGF stimulated VEGF release dose dependently in the range between 10 and 100 ng/ml. SB203580, an inhibitor of p38 MAP kinase, markedly enhanced the bFGF-induced VEGF release. bFGF induced the phosphorylation of both p42/p44 MAP kinase and p38 MAP kinase. PD98059, an inhibitor of upstream kinase of p42/p44 MAP kinase, reduced the VEGF release. SB203580 enhanced the phosphorylation of p42/p44 MAP kinase induced by bFGF. The enhancement by SB203580 of the bFGF-stimulated VEGF release was suppressed by PD98059. The depletion of extracellular Ca2+ by [ethylenebis-(oxyethylenenitrilo)]tetracetic acid (EGTA) or 1,2-bis-(O -aminophinoxy)-ethane- N,N,N,N -tetracetic acid tetracetoxymethyl ester (BAPTA/AM), a chelator of intracellular Ca2+, suppressed the bFGF-induced VEGF release. A23187, a Ca ionophore, or thapsigargin, known to induce Ca2+ release from intracellular Ca2+ store, stimulated the release of VEGF by itself. A23187 induced the phosphorylation of p42/p44 MAP kinase and p38 MAP kinase. PD98059 suppressed the VEGF release induced by A23187. SB203580 had little effect on either A23187-induced VEGF release or the phosphorylation of p42/p44 MAP kinase by A23187. These results strongly suggest that bFGF stimulates VEGF release through p42/p44 MAP kinase in osteoblasts and that the VEGF release is negatively regulated by bFGF-activated p38 MAP kinase. [source]

Divergent Regulation of Hypothalamic Neuropeptide Y and Agouti-Related Protein by Photoperiod in F344 rats With Differential Food Intake and Growth

JOURNAL OF NEUROENDOCRINOLOGY, Issue 7 2009
A. W. Ross
Hypothalamic genes involved in food intake and growth regulation were studied in F344 rats in response to photoperiod. Two sub-strains were identified: F344/NHsd (F344/N) and F344/NCrHsd (F344/NCr); sensitive and relatively insensitive to photoperiod respectively. In F344/N rats, marked, but opposite, changes in the genes for neuropeptide Y (NPY) (+97.5%) and agouti-related protein (AgRP) (,39.3%) expression in the arcuate nucleus were observed in response to short (8 : 16 h light/dark cycle, SD) relative to long (16 : 8 h light/dark cycle, LD) day photoperiods. Changes were associated with both reduced food intake and growth. Expression of the genes for cocaine and amphetamine-regulated transcript (CART) and pro-opiomelanocortin (POMC) in the arcuate nucleus was unchanged by photoperiod. POMC in the ependymal layer around the third ventricle was markedly inhibited by SD. Parallel decreases in the genes for growth hormone-releasing hormone (GHRH) and somatostatin (Somatostatin) mRNA in the arcuate nucleus and Somatostatin in the periventricular nucleus were observed in SD. Serum levels of insulin-like growth factor (IGF)-1 and insulin were lower in F344/N rats in SD, whereas neither leptin nor corticosterone levels were affected. By contrast, F344/NCr rats that show only minor food intake and growth rate changes showed minimal responses in these genes and hormones. Thus, NPY/AgRP neurones may be pivotal to the photoperiodic regulation of food intake and growth. Potentially, the SD increase in NPY expression may inhibit growth by decreasing GHRH and Somatostatin expression, whereas the decrease in AgRP expression probably leads to reduced food intake. The present study reveals an atypical and divergent regulation of NPY and AgRP, which may relate to their separate roles with respect to growth and food intake, respectively. [source]

Divergent regulation of GIRK1 and GIRK2 subunits of the neuronal G protein gated K+ channel by G,iGDP and G,,

THE JOURNAL OF PHYSIOLOGY, Issue 14 2009
Moran Rubinstein
G protein activated K+ channels (GIRK, Kir3) are switched on by direct binding of G,, following activation of Gi/o proteins via G protein-coupled receptors (GPCRs). Although G,i subunits do not activate GIRKs, they interact with the channels and regulate the gating pattern of the neuronal heterotetrameric GIRK1/2 channel (composed of GIRK1 and GIRK2 subunits) expressed in Xenopus oocytes. Coexpressed G,i3 decreases the basal activity (Ibasal) and increases the extent of activation by purified or coexpressed G,,. Here we show that this regulation is exerted by the ,inactive' GDP-bound G,i3GDP and involves the formation of G,i3,, heterotrimers, by a mechanism distinct from mere sequestration of G,,,away' from the channel. The regulation of basal and G,,-evoked current was produced by the ,constitutively inactive' mutant of G,i3, G,i3G203A, which strongly binds G,,, but not by the ,constitutively active' mutant, G,i3Q204L, or by G,,-scavenging proteins. Furthermore, regulation by G,i3G203A was unique to the GIRK1 subunit; it was not observed in homomeric GIRK2 channels. In vitro protein interaction experiments showed that purified G,, enhanced the binding of G,i3GDP to the cytosolic domain of GIRK1, but not GIRK2. Homomeric GIRK2 channels behaved as a ,classical' G,, effector, showing low Ibasal and strong G,,-dependent activation. Expression of G,i3G203A did not affect either Ibasal or G,,-induced activation. In contrast, homomeric GIRK1* (a pore mutant able to form functional homomeric channels) exhibited large Ibasal and was poorly activated by G,,. Expression of G,i3GDP reduced Ibasal and restored the ability of G,, to activate GIRK1*, like in GIRK1/2. Transferring the unique distal segment of the C terminus of GIRK1 to GIRK2 rendered the latter functionally similar to GIRK1*. These results demonstrate that GIRK1 containing channels are regulated by both G,i3GDP and G,,, while GIRK2 is a G,,-effector insensitive to G,i3GDP. [source]

Divergent regulation of cardiac KCND3 potassium channel expression by the thyroid hormone receptors ,1 and ,1

THE JOURNAL OF PHYSIOLOGY, Issue 6 2009
Natig Gassanov
The cardiac transient outward current Ito is regulated by thyroid hormone (T3). However, it remains unclear whether T3 directly modulates underlying gene transcription and which thyroid receptor (TR) isoform might be responsible for gene transactivation. To clarify this situation, we analysed the role of T3 and its receptors ,1 (TR,1) and ,1 (TR,1) in regulation of KCNA4, KCND2, KCND3 and KCNIP2 transcription in rat cardiomyocytes. Initial results demonstrated a T3-mediated increase of Ito current density. T3 stimulation enhanced KCND2 and KCND3 expression and decreased KCNA4 transcription, while KCNIP2 remained unaffected. To dissect the role of TR,1 and TR,1 in T3-dependent Ito modulation, TR,1 and TR,1 were overexpressed in cardiomyocytes by adenovirus-mediated gene transfer. TR,1 increased Ito, while TR,1 significantly reduced Ito in size, which was associated with TR,1-mediated increase and TR,1-mediated reduction of KCND2/3 transcription. To further evaluate a possible direct interaction of TR,1 and TR,1 with the KCND3 promoter, TR expression vectors were cotransfected with a construct containing 2335 bp of the KCND3 5,-flanking sequence linked to a luciferase reporter into ventricular myocytes. While the TR,1 aporeceptor enhanced KCND3 transcription, the TR,1 aporeceptor suppressed KCND3 expression, with both effects exhibiting ligand-dependent amplification upon T3 stimulation. Deletion of the KCND3 5,-flanking region localized the suppressible promoter sequence for TR,1 to within ,293 bp and the activating promoter sequence for TR,1 to within ,2335 to ,1654 bp of the transcription start site. Disruption of putative TR binding sites by mutagenesis abolished the TR,1- (G-1651T) and TR,1- (G-73T) mediated effects, indicating that TR,1 and TR,1 response elements map to different regions of the KCND3 promoter. Thus, Ito is modulated by diverse T3-dependent regulation of underlying gene transcription. TR,1 and TR,1 exhibit distinct effects on KCND3 transactivation with TR,1 enhancing and TR,1 suppressing KCND3 transcription. [source]