共查询到20条相似文献,搜索用时 31 毫秒
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目的通过胰岛素和磷脂酰肌醇-3激酶(P13K)抑制剂渥曼青霉素(wortmannin)对P13K/丝氨酸苏氨酸蛋白激酶(P13K/Akt)信号通路的激活和抑制作用,观察P13K/Akt信号通路对海马神经元β-淀粉样前体蛋白裂解酶1(BACEl)mRNA水平表达的影响。方法20只sD大鼠随机分为空白对照组、假手术组、胰岛素组和渥曼青霉素组,海马立体定向注射胰岛素和P13K抑制剂渥曼青霉素。逆转录一聚合酶链反应(RT-PCR)检测P13K/Akt信号传导下游蛋白Akt以及BACEImRNA水平。结果注射胰岛素的海马P13K信号通路下游信号分子:AktmRNA表达上调(分别较空白和阴性对照组P=0.047,P=0.002),而BACElmRNA表达下调(分别较空白和阴性对照组P=0.004,P=0.01)。渥曼青霉素组的P13K下游信号分子AktmRNA表达明显被抑制(分别较空白和阴性对照组P=0.002,P=0.039),同时BACEImRNA的表达较对照组上调(分别较空白和阴性对照组P=0.039,P=0.018)。结论胰岛素信号通路P13K/AM可以调节BACEl的转录水平参与阿尔茨海默病的发病机制。 相似文献
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As master gene regulators, microRNAs are involved in diverse cellular pathways. It is well known that microRNAs are often dysregulated in many types of cancer and other human diseases. In cancer, microRNAs may function as oncogenes or tumor suppressors. Interestingly, recent evidence suggests that microRNA-mediated gene regulation interconnects with the Akt pathway, forming an Akt–microRNA regulatory network. MicroRNAs and Akt in this network work together to exert their cellular functions. Thus, a better understanding of this Akt–microRNA regulatory network is critical to successful targeting of the PI3K/Akt pathway for cancer therapy. We review recent advances in the understanding of how microRNAs affect Akt activity as well as how microRNAs are regulated through the Akt pathway. We also briefly discuss the clinical implication of gene regulation mediated through Akt-associated microRNAs. 相似文献
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Liu ZM Chen GG Vlantis AC Tse GM Shum CK van Hasselt CA 《Cellular and molecular life sciences : CMLS》2007,64(11):1428-1436
The molecular mechanism responsible for cadmium-induced cell death in thyroid cancer cells (FRO) is unknown. We demonstrated
that apoptosis of FRO cells induced by cadmium was concentration and time dependent. Cadmium caused the rapid elevation of
intracellular calcium and induced phosphorylation of Akt, p53, JNK, ERK and p38. Inhibition of PI3K/Akt attenuated the cadmium-induced
apoptosis, but the inhibition of JNK inhibitor, ERK or p38 aggravated it, indicating that activation of PI3K/Akt was a pro-apoptosis
signal in response to cadmium treatment, whereas the activation of stress-activated protein kinase JNK, ERK and p38 functioned
as survival signals to counteract the cadmium-induced apoptosis. Buffering of the calcium response attenuated mitochondrial
impairment, recovered the cadmium-activated Akt, p53, JNK, ERK and p38, and subsequently blocked the apoptosis. These results
suggested that apoptosis induced by cadmium in FRO cells was initiated by the rapid elevation of intracellular calcium, followed
by calcium-mediated activation of PI3K/Akt and mitochondrial impairment.
Received 28 February 2007; received after revision 2 April 2007; accepted 23 April 2007 相似文献
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PIAS/SUMO: new partners in transcriptional regulation 总被引:19,自引:0,他引:19
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Kim SH Juhnn YS Kang S Park SW Sung MW Bang YJ Song YS 《Cellular and molecular life sciences : CMLS》2006,63(7-8):930-938
The E5 oncoprotein of human papillomavirus (HPV) 16 plays an important role in early cervical carcinogenesis. Vascular endothelial
growth factor (VEGF) plays a central role in switching on the angiogenic phenotype during early cervical carcinogenesis. However,
the relationship between E5 and VEGF has not previously been examined. To clarify the regulatory role of E5 in VEGF expression,
we transferred the E5 gene into various cell types. E5 increased VEGF expression. The addition of epidermal growth factor
receptor (EGFR) inhibitor significantly suppressed VEGF expression, demonstrating that E5 stimulates VEGF expression through
the activation of EGFR. E5-mediated EGFR activation was accompanied by phosphorylation of Akt and ERK1/2, which are also involved
in VEGF expression. Furthermore, the mRNA stability of VEGF was not affected by E5, but VEGF promoter activity could be modulated
by inhibitors of the EGFR, MEK-ERK1/2 and PI3K/Akt pathways in E5-expressing cells. Collectively, these novel results suggest
that HPV 16 E5 increases VEGF expression by activating EGFR, MEK/ERK1/2 and PI3K/Akt.
Received 23 November 2005; received after revision 10 January 2006; accepted 9 February 2006 相似文献
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Gerardo Rodriguez-Araujo Hironori Nakagami Hiroki Hayashi Masaki Mori Tetsuya Shiuchi Yasuhiko Minokoshi Yoshikazu Nakaoka Yoichi Takami Issei Komuro Ryuichi Morishita Yasufumi Kaneda 《Cellular and molecular life sciences : CMLS》2013,70(6):1123-1133
Insulin is the main glucoregulator that promotes the uptake of glucose by tissues and the subsequent utilization of glucose as an energy source. In this paper, we describe a novel glucoregulator, the alpha-synuclein (SNCA) protein, that has previously been linked to Parkinson’s disease. Treatment with recombinant SNCA promotes glucose uptake in vitro in preadipocytes and in vivo in the adipose tissues and skeletal muscles of mice through the LPAR2/Gab1/PI3K/Akt pathway; these effects occur independently of the insulin receptor. This function of SNCA represents a new mechanistic insight that creates novel avenues of research with respect to the process of glucose regulation. 相似文献
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The rapid migration of intestinal epithelial cells (IEC) is important for the healing of mucosal wounds. We have previously
shown that polyamine depletion inhibits migration of IEC-6 cells. Akt activation and its downstream target GSK-3β have been
implicated in the regulation of migration. Here we investigated the significance of elevated phosphatidylinositol 3-kinase
(PI3K)/Akt signaling on migration of polyamine-depleted cells. Polyamine-depleted cells had high Akt (Ser473) and GSK-3β (Ser9)
phosphorylation. Pretreatment with 20 μM LY294002 (PI3K inhibitor) for 30 min inhibited phosphorylation of Akt, increased
migration by activating Rac1 in polyamine-depleted IEC-6 cells, and restored the actin structure similar to that in cells
grown in control medium. Treatment of cells with a GSK-3β inhibitor (AR-A014418) altered the actin cytoskeleton and inhibited
migration, mimicking the effects of polyamine depletion. Thus, our results indicate that sustained activation of Akt in response
to polyamine depletion inhibits migration through GSK-3β and Rac1.
Received 25 August 2006; received after revision 3 October 2006; accepted 16 October 2006 相似文献
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S. P. Yun M. Y. Lee J. M. Ryu H. J. Han 《Cellular and molecular life sciences : CMLS》2009,66(9):1603-1616
Identifying the small molecules that permit precise regulation of embryonic stem (ES) cell proliferation should further support
our understanding of the underlying molecular mechanisms of self renewal. In the present study, we showed that PGE2 increased [3H]-thymidine incorporation in a time and dose dependent manner. In addition, PGE2 increased the expression of cell cycle regulatory proteins, the percentage of cells in S phase and the total number of cells.
PGE2 obviously increased E-type prostaglandin (EP) receptor 1 mRNA expression level compare to 2, 3, 4 subtypes. EP1 antagonist
also blocked PGE2-induced cell cycle regulatory protein expression and thymidine incorporation. PGE2 caused phosphorylation of protine kinase C, Src, epidermal growth factor (EGF) receptor, phosphatidylinositol 3-kinase (PI3K)/Akt
phosphorylation, and p44/42 mitogen-activated protein kinase (MAPK), which were blocked by each inhibitors. In conclusion,
PGE2-stimulated proliferation is mediated by MAPK via EP1 receptor-dependent PKC and EGF receptor-dependent PI3K/Akt signaling
pathways in mouse ES cells.
Received 30 January 2009; received after revision 03 March 2009; accepted 10 March 2009 相似文献
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Astrid Musnier Domitille Heitzler Thomas Boulo Sophie Tesseraud Guillaume Durand Charlotte Lécureuil Hervé Guillou Anne Poupon Eric Reiter Pascale Crépieux 《Cellular and molecular life sciences : CMLS》2009,66(21):3487-3503
The mechanisms whereby G protein-coupled receptors (GPCR) activate signalling pathways involved in mRNA translation are ill-defined,
in contrast to tyrosine kinase receptors (TKR). We compared a GPCR and a TKR, both endogenously expressed, for their ability
to mediate phosphorylation of 70-kDa ribosomal S6 kinase p70S6K in primary rat Sertoli cells at two developmental stages.
In proliferating cells stimulated with follicle-stimulating hormone (FSH), active p70S6K was phosphorylated on T389 and T421/S424,
through cAMP-dependent kinase (PKA) and phosphatidyl-inositide-3 kinase (PI3K) antagonizing actions. In FSH-stimulated differentiating
cells, active p70S6K was phosphorylated solely on T389, PKA and PI3K independently enhancing its activity. At both developmental
stages, insulin-induced p70S6K regulation was consistent with reported data. Therefore, TKR and GPCR trigger distinct p70S6K
active conformations. p70S6K developmental regulation was formalized in a dynamic mathematical model fitting the data, which
led to experimentally inaccessible predictions on p70S6K phosphorylation rate. 相似文献
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Phosphatidylinositol 3-kinase (PI3-kinase) activity has been implicated in regulating cell cycle progression at distinct points
in the cell cycle by preventing cell cycle arrest or apoptosis. In this study, the role of PI3-kinase activity during the
entire G1 phase of the ongoing cell cycle was studied in Chinese hamster ovary (CHO) cells synchronized by mitotic shake-off.
We show that inhibition of PI3-kinase activity during and 2 h after mitosis inhibited cell cycle progression into S phase.
In the presence of the PI3-kinase inhibitor wortmannin or LY294002, cells were arrested during early G1 phase, leading to
the expression of the cleaved caspase-3, a central mediator of apoptosis. These results demonstrate that PI3-kinase activity
is required for progression through the M/G1 phase. In the absence of PI3-kinase activity, cells are induced for apoptosis
in this particular phase of the cell cycle.
Received 7 September 2005; received after revision 26 October 2005; accepted 11 November 2005 相似文献
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Facchin S Ruzzene M Peggion C Sartori G Carignani G Marin O Brustolon F Lopreiato R Pinna LA 《Cellular and molecular life sciences : CMLS》2007,64(19-20):2680-2689
p53-related protein kinase (PRPK), the human homologue of yeast Bud32, belonging to a small subfamily of atypical protein kinases, is inactive unless it is previously incubated with cell lysates. Here we show that such an activation of PRPK is mediated by another kinase, Akt/PKB, which phosphorylates PRPK at Ser250. We show that recombinant PRPK is phosphorylated in vitro by Akt and its phospho-form is recognized by a Ser250-phospho-specific antibody; that cell co-transfection with Akt along with wild-type PRPK, but not with its Ser250Ala mutant, results in increased PRPK phosphorylation; and that the phosphorylation of p53 at Ser15, the only known substrate of PRPK, is markedly increased by co-transfection of Akt with wild-type PRPK, but not PRPK dead mutant, and is abrogated by cell treatment with the Akt pathway inhibitor LY294002. Our data disclose an unanticipated mechanism by which PRPK can be activated and provide a functional link between this enigmatic kinase and the Akt signaling pathway. 相似文献
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Muñoz U Bartolomé F Esteras N Bermejo-Pareja F Martín-Requero A 《Cellular and molecular life sciences : CMLS》2008,65(21):3507-3519
It has been proposed that neuroinflammation, among other factors, may trigger an aberrant neuronal cell cycle re-entry leading
to neuronal death. Cell cycle disturbances are also detectable in peripheral cells from Alzheimer’s disease (AD) patients.
We previously reported that the anti-inflammatory 15- deoxy-Δ12,14-prostaglandin J
2 (15d-PGJ
2) increased the cellular content of the cyclin-dependent kinase inhibitor p27, in lymphoblasts from AD patients. This work
aimed at elucidating the mechanisms of 15d-PGJ
2-induced p27 accumulation. Phosphorylation, half-life, and the nucleo-cytoplasmic traffic of p27 protein were altered by 15d-PGJ2
by mechanisms dependent on PI3K/Akt activity. 15d-PGJ
2 prevents the calmodulin-dependent Akt overactivation in AD lymphoblasts by blocking its binding to the 85-kDa regulatory
subunit of PI3K. These effects of 15d-PGJ
2 were not mimicked by 9,10-dihydro-15-deoxy-Δ12,14- prostaglandin J
2, suggesting that 15d-PGJ
2 acts independently of peroxisome proliferator-activated receptor γ activation and that the α,β-unsaturated carbonyl group
in the cyclopentenone ring of 15d-PGJ
2 is a requisite for the observed effects.
Received 14 July 2008; received after revision 2 September 2008; accepted 12 September 2008 相似文献
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Glycogen synthase kinase 3β and Alzheimer’s disease: pathophysiological and therapeutic significance 总被引:3,自引:0,他引:3
Balaraman Y Limaye AR Levey AI Srinivasan S 《Cellular and molecular life sciences : CMLS》2006,63(11):1226-1235
Alzheimer’s disease (AD) is a neurodegenerative disorder associated with cognitive and behavioral dysfunction and is the leading
cause of dementia in the elderly. Several studies have implicated molecular and cellular signaling cascades involving the
serine-threonine kinase, glycogen synthase kinase β(GSK-3β) in the pathogenesis of AD. GSK-3β may play an important role in
the formation of neurofibrillary tangles and senile plaques, the two classical pathological hallmarks of AD. In this review,
we discuss the interaction between GSK-3β and several key molecules involved in AD, including the presenilins, amyloid precursor
protein, tau, and β-amyloid. We identify the signal transduction pathways involved in the pathogenesis of AD, including Wnt,
Notch, and the PI3 kinase/Akt pathway. These may be potential therapeutic targets in AD.
Received 19 December 2005; received after revision 24 January 2006; accepted 6 February 2006 相似文献