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61.
Qi J Lang W Geisler JG Wang P Petrounia I Mai S Smith C Askari H Struble GT Williams R Bhanot S Monia BP Bayoumy S Grant E Caldwell GW Todd MJ Liang Y Gaul MD Demarest KT Connelly MA 《Journal of lipid research》2012,53(6):1106-1116
Diacylglycerol acyltransferase (DGAT) catalyzes the final step in triglyceride (TG) synthesis. There are two isoforms, DGAT1 and DGAT2, with distinct protein sequences and potentially different physiological functions. To date, the ability to determine clear functional differences between DGAT1 and DGAT2, especially with respect to hepatic TG synthesis, has been elusive. To dissect the roles of these two key enzymes, we pretreated HepG2 hepatoma cells with (13)C(3)-D(5)-glycerol or (13)C(18)-oleic acid, and profiled the major isotope-labeled TG species by liquid chromatography tandem mass spectrometry. Selective DGAT1 and DGAT2 inhibitors demonstrated that (13)C(3)-D(5)-glycerol-incorporated TG synthesis was mediated by DGAT2, not DGAT1. Conversely, (13)C(18)-oleoyl-incorporated TG synthesis was predominantly mediated by DGAT1. To trace hepatic TG synthesis and VLDL triglyceride (VLDL-TG) secretion in vivo, we administered D(5)-glycerol to mice and measured plasma levels of D(5)-glycerol-incorporated TG. Treatment with an antisense oligonucleotide (ASO) to DGAT2 led to a significant reduction in D(5)-glycerol incorporation into VLDL-TG. In contrast, the DGAT2 ASO had no effect on the incorporation of exogenously administered (13)C(18)-oleic acid into VLDL-TG. Thus, our results indicate that DGAT1 and DGAT2 mediate distinct hepatic functions: DGAT2 is primarily responsible for incorporating endogenously synthesized FAs into TG, whereas DGAT1 plays a greater role in esterifying exogenous FAs to glycerol. 相似文献
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Giammarino A Manera M Robbe D Perugini M Amorena M 《Animal reproduction science》2009,112(3-4):325-333
The aim of this study was to evaluate, in vitro, the effects of increasing concentrations of GnRH on spontaneous mechanical activity patterns of uterine smooth muscle preparations of cows during the follicular and the luteal phases of the oestrus cycle. Uterine smooth muscle strips from 14 cows in follicular and 9 in luteal phase were collected immediately after slaughter and processed within 60 min from collection. Two strips of the same uterus were mounted in an isolated organ bath with two chambers to evaluate the role of decapeptide GnRH on spontaneous myometrial contractility. After equilibration period at 20 mN resting tension, the mechanical activity of the uterus was recorded for 10 min and the mean contractile force (MCF) was calculated. Then GnRH antagonist (antide) was added to one chamber at fixed concentration (10(-4)mol) and allowed to diffuse in solution and make contact with the strips. Subsequently, GnRH was added to the two baths at the same time at increasing concentration and MCF was recorded for 10 min. The effect of GnRH on spontaneous myometrial activity was evident only in the strips from subjects in follicular phase. Our results are suggestive of the presence of GnRH receptors in bovine myometrial tissue. The involvement of GnRH on uterine contractions at mating can be postulated. 相似文献
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Carlucci A Porpora M Garbi C Galgani M Santoriello M Mascolo M di Lorenzo D Altieri V Quarto M Terracciano L Gottesman ME Insabato L Feliciello A 《The Journal of biological chemistry》2010,285(50):39260-39270
PTPD1, a cytosolic non-receptor protein-tyrosine phosphatase, stimulates the Src-EGF transduction pathway. Localization of PTPD1 at actin cytoskeleton and adhesion sites is required for cell scattering and migration. Here, we show that during EGF stimulation, PTPD1 is rapidly recruited to endocytic vesicles containing the EGF receptor. Endosomal localization of PTPD1 is mediated by interaction with KIF16B, an endosomal kinesin that modulates receptor recycling at the plasma membrane. Silencing of PTPD1 promotes degradation of EGF receptor and inhibits downstream ERK signaling. We also found that PTPD1 is markedly increased in bladder cancer tissue samples. PTPD1 levels positively correlated with the grading and invasiveness potential of these tumors. Transgenic expression of an inactive PTPD1 mutant or genetic knockdown of the endogenous PTPD1 severely inhibited both growth and motility of human bladder cancer cells. These findings identify PTPD1 as a novel component of the endocytic machinery that impacts on EGF receptor stability and on growth and motility of bladder cancer cells. 相似文献
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Caspase activation in etoposide-treated fibroblasts is correlated to ERK phosphorylation and both events are blocked by polyamine depletion 总被引:2,自引:0,他引:2
Stefanelli C Tantini B Fattori M Stanic' I Pignatti C Clo C Guarnieri C Caldarera CM Mackintosh CA Pegg AE Flamigni F 《FEBS letters》2002,527(1-3):223-228
Activation of the extracellular signal-regulated kinases (ERKs) 1 and 2 is correlated to cell survival, but in some cases ERKs can act in signal transduction pathways leading to apoptosis. Treatment of mouse fibroblasts with 20 microM etoposide elicited a sustained phosphorylation of ERK 1/2, that increased until 24 h from the treatment in parallel with caspase activity. The inhibitor of ERK activation PD98059 abolished caspase activation, but caspase inhibition did not reduce ERK 1/2 phosphorylation, suggesting that ERK activation is placed upstream of caspases. Both ERK and caspase activation were blocked in cells depleted of polyamines by the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO). In etoposide-treated cells, DFMO also abolished phosphorylation of c-Jun NH(2)-terminal kinases triggered by the drug. Polyamine replenishment with exogenous putrescine restored the ability of the cells to undergo caspase activation and ERK 1/2 phosphorylation in response to etoposide. Ornithine decarboxylase activity decreased after etoposide, indicating that DFMO exerts its effect by depleting cellular polyamines before induction of apoptosis. These results reveal a role for polyamines in the transduction of the death signal triggered by etoposide. 相似文献
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Alzheimer amyloid precursor protein (APP) is the precursor for the Abeta peptide involved in pathogenesis of Alzheimer's disease. The soluble ectodomain fragment of APP (sAPP) functions as a growth factor for epithelial cells, suggesting an important function for APP outside neuronal tissue. Previous studies have shown that in polarized epithelial cells, APP is targeted to the basolateral domain. Tyr653 within the cytoplasmic tail of APP mediates the basolateral targeting of APP, but the sorting machinery that binds to this residue has largely remained unknown. In this study, we analyzed the role of adaptor complexes in the polarized sorting of APP. We show that the medium subunit mu1B of the epithelia-specific adaptor protein (AP)-1B binds onto the cytoplasmic tail of APP in a Tyr653-dependent way. Moreover, ectopic expression of mu1B in cells lacking AP-1B resulted in correction of apical missorting of wild-type but not Tyr653Ala APP. Basolateral secretion of sAPP was found to be independent of Tyr653. We propose a model for polarized targeting of APP according to which sorting of APP to basolateral domain is dependent on binding of AP-1B on Tyr653 in basolateral endosomes. This model is in accordance with the current understanding of sorting mechanisms mediating polarized targeting of membrane proteins. 相似文献