磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子...磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.展开更多
Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly...Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligandoccupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.展开更多
Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of ...Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra.Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR.Therefore,this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra.Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion.Cerebral infarct volume was measured using 2%TTC staining.TUNEL staining was conducted to evaluate neuronal apoptosis.Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway.The results suggested that resveratrol significantly improved neurological function,reduced cerebral infarct volume,decreased neuronal damage,and markedly attenuated neuronal apoptosis;these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490.We also found that resveratrol significantly upregulated the expression of p-JAK2,p-STAT3,p-AKT,p-mTOR,and BCL-2 and downregulated expression of cleaved caspase-3 and BAX,which was partially reversed by LY294002 and AG490.These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury,which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR.Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.展开更多
The mammalian target of rapamycin （mTOR） has drawn growth control and its involvement in human tumorigenesis much attention recently because of its essential role in cell Great endeavors have been made to elucidate ...The mammalian target of rapamycin （mTOR） has drawn growth control and its involvement in human tumorigenesis much attention recently because of its essential role in cell Great endeavors have been made to elucidate the functions and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental biological processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including growth factors, nutrients, energy levels, and cellular stress. The significance of roTOR has been highlighted most recently by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells but also further complicate the regulation network. Thus, it is now even more critical that we precisely understand the underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the mTOR signaling pathway. In this review, we will discuss different mTOR-associated proteins, the regulation of mTOR complexes, and the consequences of mTOR dysregulation under pathophysiological conditions.展开更多
The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a c...The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma （RCC） is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.展开更多
Sevoflurane postconditioning reduces myocardial infarct size.The objective of this study was to examine the role of the phosphatidylinositol-3-kinase(PI3K)/Akt pathway in anesthetic postconditioning and to determine w...Sevoflurane postconditioning reduces myocardial infarct size.The objective of this study was to examine the role of the phosphatidylinositol-3-kinase(PI3K)/Akt pathway in anesthetic postconditioning and to determine whether PI3K/Akt signaling modulates the expression of pro-and antiapoptotic proteins in sevoflurane postconditioning.Isolated and perfused rat hearts were prepared first,and then randomly assigned to the following groups:Sham-operation(Sham),ischemia/reperfusion(Con),sevoflurane postconditioning(SPC),Sham plus 100 nmol/L wortmannin(Sham+Wort),Con+Wort,SPC+Wort,and Con+dimethylsulphoxide(DMSO).Sevoflurane postconditioning was induced by administration of sevoflurane(2.5%,v/v) for 10 min from the onset of reperfusion.Left ventricular developed pressure(LVDP),left ventricular end-diastolic pressure(LVEDP),maximum increase in rate of LVDP(+dP/dt),maximum decrease in rate of LVDP(?dP/dt),heart rate(HR),and coronary flow(CF) were measured at baseline,R30 min(30 min of reperfusion),R60 min,R90 min,and R120 min.Creatine kinase(CK) and lactate dehydrogenase(LDH) were measured after 5 min and 10 min reperfusion.Infarct size was determined by triphenyltetrazolium chloride staining at the end of reperfusion.Total Akt and phosphorylated Akt(phospho-Akt),Bax,Bcl-2,Bad,and phospho-Bad were determined by Western blot analysis.Analysis of variance(ANOVA) and Student-Newman-Keuls' test were used to investigate the significance of differences between groups.The LVDP,±dP/dt,and CF were higher and LVEDP was lower in the SPC group than in the Con group at all points of reperfusion(P<0.05).The SPC group had significantly reduced CK and LDH release and decreased infarct size compared with the Con group [(22.9±8)% vs.(42.4±9.4)%,respectively;P<0.05].The SPC group also had increased the expression of phospho-Akt,Bcl-2,and phospho-Bad,and decreased the expression of Bax.Wortmannin abolished the cardioprotection of sevoflurane postconditioning.Sevoflurane postconditioning may protect the isolated rat heart.Activation of PI3K展开更多
文摘磷脂酰肌醇3-激酶(PI3Ks)作为酪氨酸激酶和G蛋白偶联受体的主要下游分子,通过催化产生第二信使3,4,5-三磷酸磷脂酰肌醇(PIP3)并激活Akt、糖原合酶激酶-3(GSK-3)、Forkhead转录因子FoxO1、mTOR(mammalian target of rapamycin)等下游分子,将多种生长因子及细胞因子的信号传递到细胞内,从而对细胞增殖、分化、凋亡和葡萄糖转运等多种生物过程起重要的调节作用.PTEN(phosphatase and tensin homologue)是PI3K信号通路的重要负调节因子.本文将对PI3K-Akt信号通路在糖代谢中的作用予以简要综述.
文摘Transforming growth factor-β utilizes a multitude of intracellular signaling pathways in addition to Smads to regulate a wide array of cellular functions. These non-canonical, non-Smad pathways are activated directly by ligandoccupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. These non-Smad pathways include various branches of MAP kinase pathways, Rho-like GTPase signaling pathways, and phosphatidylinositol-3-kinase/AKT pathways. This review focuses on recent advances in the understanding of the molecular and biochemical mechanisms of non-Smad pathways. In addition, functions of these non-Smad pathways are also discussed.
基金supported by the Foundation for Science and Technology Research Project of Chongqing(cstc2012ggB1002).
文摘Ischemic stroke is a common disease with high mortality and morbidity worldwide.One of the important pathophysiological effects of ischemic stroke is apoptosis.A neuroprotective effect is defined as the inhibition of neuronal apoptosis to rescue or delay the infarction in the surviving ischemic penumbra.Resveratrol is a natural polyphenol that reportedly prevents cerebral ischemia injury by regulating the expression of PI3K/AKT/mTOR.Therefore,this study aimed to elucidate the neuroprotective effect of resveratrol on cerebral ischemia/reperfusion injury and to investigate the signaling pathways and mechanisms through which resveratrol regulates apoptosis in the ischemic penumbra.Rats were subjected to middle cerebral artery occlusion for 2 h followed by 24 h reperfusion.Cerebral infarct volume was measured using 2%TTC staining.TUNEL staining was conducted to evaluate neuronal apoptosis.Western blotting and immunohistochemistry were used to detect the proteins involved in the JAK2/STAT3/PI3K/AKT/mTOR pathway.The results suggested that resveratrol significantly improved neurological function,reduced cerebral infarct volume,decreased neuronal damage,and markedly attenuated neuronal apoptosis;these effects were attenuated by the inhibition of PI3K/AKT with LY294002 and JAK2/STAT3 with AG490.We also found that resveratrol significantly upregulated the expression of p-JAK2,p-STAT3,p-AKT,p-mTOR,and BCL-2 and downregulated expression of cleaved caspase-3 and BAX,which was partially reversed by LY294002 and AG490.These results suggested that resveratrol provides a neuroprotective effect against cerebral ischemia/reperfusion injury,which is partially mediated by the activation of JAK2/STAT3 and PI3K/AKT/mTOR.Resveratrol may indirectly upregulate the PI3K/AKT/mTOR pathway by activating JAK2/STAT3.
文摘The mammalian target of rapamycin （mTOR） has drawn growth control and its involvement in human tumorigenesis much attention recently because of its essential role in cell Great endeavors have been made to elucidate the functions and regulation of mTOR in the past decade. The current prevailing view is that mTOR regulates many fundamental biological processes, such as cell growth and survival, by integrating both intracellular and extracellular signals, including growth factors, nutrients, energy levels, and cellular stress. The significance of roTOR has been highlighted most recently by the identification of mTOR-associated proteins. Amazingly, when bound to different proteins, mTOR forms distinctive complexes with very different physiological functions. These findings not only expand the roles that mTOR plays in cells but also further complicate the regulation network. Thus, it is now even more critical that we precisely understand the underlying molecular mechanisms in order to directly guide the development and usage of anti-cancer drugs targeting the mTOR signaling pathway. In this review, we will discuss different mTOR-associated proteins, the regulation of mTOR complexes, and the consequences of mTOR dysregulation under pathophysiological conditions.
基金supported by the grant from The University of Texas MD Anderson Cancer Center Kidney Cancer Multidisciplinary Research Program to ZDthe NCI CCSG grant(No. P30 CA016672)the GDAC grant(No.5U24CA143883)
文摘The phosphatidylinositol 3 kinase （PI3K）/AKT pathway is genetically targeted in more pathway components and in more tumor types than any other growth factor signaling pathway, and thus is frequently activated as a cancer driver. More importantly, the PI3K/AKT pathway is composed of multiple bifurcating and converging kinase cascades, providing many potential targets for cancer therapy. Renal cell carcinoma （RCC） is a high-risk and high-mortality cancer that is notoriously resistant to traditional chemotherapies or radiotherapies. The PI3K/AKT pathway is modestly mutated but highly activated in RCC, representing a promising drug target. Indeed, PI3K pathway inhibitors of the rapalog family are approved for use in RCC. Recent large-scale integrated analyses of a large number of patients have provided a molecular basis for RCC, reiterating the critical role of the PI3K/AKT pathway in this cancer. In this review, we summarize the genetic alterations of the PI3K/AKT pathway in RCC as indicated in the latest large-scale genome sequencing data, as well as treatments for RCC that target the aberrant activated PI3K/AKT pathway.
基金supported by the National Natural Science Foundation of China (No. 30772090)the Natural Science Foundation of Zhejiang Province (Nos. Y204141 and R2090259)+1 种基金the Foundation from Science and Technology Department of Zhejiang Province (No. 2007R10034)the Foundation from the Health Bureau of Zhejiang Province (No. 2007QN007),China
文摘Sevoflurane postconditioning reduces myocardial infarct size.The objective of this study was to examine the role of the phosphatidylinositol-3-kinase(PI3K)/Akt pathway in anesthetic postconditioning and to determine whether PI3K/Akt signaling modulates the expression of pro-and antiapoptotic proteins in sevoflurane postconditioning.Isolated and perfused rat hearts were prepared first,and then randomly assigned to the following groups:Sham-operation(Sham),ischemia/reperfusion(Con),sevoflurane postconditioning(SPC),Sham plus 100 nmol/L wortmannin(Sham+Wort),Con+Wort,SPC+Wort,and Con+dimethylsulphoxide(DMSO).Sevoflurane postconditioning was induced by administration of sevoflurane(2.5%,v/v) for 10 min from the onset of reperfusion.Left ventricular developed pressure(LVDP),left ventricular end-diastolic pressure(LVEDP),maximum increase in rate of LVDP(+dP/dt),maximum decrease in rate of LVDP(?dP/dt),heart rate(HR),and coronary flow(CF) were measured at baseline,R30 min(30 min of reperfusion),R60 min,R90 min,and R120 min.Creatine kinase(CK) and lactate dehydrogenase(LDH) were measured after 5 min and 10 min reperfusion.Infarct size was determined by triphenyltetrazolium chloride staining at the end of reperfusion.Total Akt and phosphorylated Akt(phospho-Akt),Bax,Bcl-2,Bad,and phospho-Bad were determined by Western blot analysis.Analysis of variance(ANOVA) and Student-Newman-Keuls' test were used to investigate the significance of differences between groups.The LVDP,±dP/dt,and CF were higher and LVEDP was lower in the SPC group than in the Con group at all points of reperfusion(P<0.05).The SPC group had significantly reduced CK and LDH release and decreased infarct size compared with the Con group [(22.9±8)% vs.(42.4±9.4)%,respectively;P<0.05].The SPC group also had increased the expression of phospho-Akt,Bcl-2,and phospho-Bad,and decreased the expression of Bax.Wortmannin abolished the cardioprotection of sevoflurane postconditioning.Sevoflurane postconditioning may protect the isolated rat heart.Activation of PI3K
