p-Akt和P27的生物学特性及其与鼻咽癌关系的研究进展

蛋白激酶B（PKB／Akt）磷酸化后激活为p-Akt,可以促进细胞存活、抑制细胞凋亡,并调控与细胞周期相关的蛋白,磷酸肌醇3-激酶（P13K）／AKT信号转导通路促进恶性肿瘤转移。P27蛋白作为细胞周期负性调控因子,能抑制各种细胞周期蛋白和激酶的活性。P27表达下降或者缺失,促进了肿瘤的增殖和侵袭。两者都在鼻咽癌的发病和转移中起作用,并对预后有影响。     

PI3K-Akt/PKB信号通路与胰岛β细胞功能

磷脂酰肌醇3激酶-蛋白激酶B/Akt(PI3K-Akt/PKB)介导β细胞的生存通路近来较受关注。PI3K-Akt/PKB信号通路是细胞内重要的信号转导通路,与细胞生长、增殖、分化、凋亡等密切相关。PI3K-Akt/PKB信号通路激活通过下游效应分子促进β细胞增殖、生长调节、增强β细胞抗凋亡功能,改善β细胞生存。调节该通路PI3K、Akt/PKB及其上下游靶位点,可能为2型糖尿病的防治提供广阔前景。     

FOXO转录因子在脑缺血后神经元凋亡诱导中的作用

蛋白激酶B(protein kinase B,PKB,亦即Akt)作为一类丝氨酸/苏氨酸激酶,调控细胞的许多重要功能,如细胞凋亡、细胞周期调控和糖代谢等.Akt/PKB执行这些功能,主要是通过磷酸化一系列下游底物完成的.作为Akt的重要底物之一,FOXO转录因子在调控细胞周期和细胞凋亡中的作用越来越多地引起重视.FOXO转录因子主要受磷脂酰肌醇3-激酶/Akt信号通路磷酸化的调节,并伴随有业细胞分布的重新定位.文章就FOXO转录因子在脑缺血后神经元凋亡中的作用做了综述.     

敲减LncRNA TPT1-AS1抑制肝癌细胞侵袭及迁移

背景长链非编码RNA(long non-coding RNA,lncRNA)肿瘤蛋白翻译调节因子1-反义RNA1(tumor protein translationally controlled regulator 1-antisence RNA 1,TPT1-AS1)TPT1-AS1可通过不同的作用方式影响肿瘤的侵袭转移,但其在肝癌中的具体作用和相关作用机制还有待进一步的实验验证.目的探讨lncRNA TPT1-AS1在肝癌中的表达及其对肝癌细胞侵袭迁移能力的影响.方法实时荧光定量PCR检测肝癌组织及肝癌细胞系(Huh7、SMMC-7721、HCCLM3和HepG2)中lncRNA TPT1-AS1的表达.靶向TPT1-AS1的小分子干扰RNA(siRNA targeted for TPT1-AS1,si-TPT1-AS1)转染后,经Transwell实验和划痕实验检测HepG2细胞侵袭及迁移能力的变化;Western blot评估上皮-间充质转分化进程(epithelial-mesenchymal transition,EMT)以及磷酸肌醇3激酶(phosphotylinosital 3 kinase,PI3K)/蛋白激酶B(protein kinase B,PKB/AKT)信号通路的活性.结果肝癌组织及肝癌细胞系(Huh7、SMMC-7721、HCCLM3和HepG2)中均可检测到lncRNA TPT1-AS1的高表达.转染siRNA-TPT1-AS1可抑制肝癌细胞HepG2的侵袭及迁移,同时抑制HepG2细胞的EMT进程.此外,下调lncRNA TPT1-AS1可抑制MMP-9的表达及PI3K/AKT信号通路的活性.结论LncRNA TPT1-AS1在肝癌中高表达.敲减lncRNA TPT1-AS1可抑制肝癌细胞HepG2的侵袭迁移,其作用机制可能与下调PI3K/AKT信号通路的活性以及下游基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)的表达,进而抑制细胞的EMT进程有关.     

新的抗肿瘤靶点Akt与胰腺癌分子靶向治疗

Akt/PKB是一种丝氨酸/苏氨酸蛋白激酶,属于cAMP依赖的蛋白激酶A、蛋白激酶G、蛋白激酶C(AGC)超家族,它是PI3K/Akt通路中的关键分子,通过磷酸化mTOR、Bad、GSK3、mdm2、caspase家族、Forkhead家族等多种作用底物,在促进肿瘤细胞的生长、增殖,抑制细胞凋亡,促使细胞侵袭和转移,促进血管生成,抵抗化疗和放疗中细胞的凋亡等方面起重要作用[1].最近在许多人类肿瘤中发现,PKB/Akt信号通路异常与肿瘤发生、发展关系密切,Akt可能成为抗肿瘤治疗的一个新靶点.胰腺癌的发生与表皮生长因子受体(EGFR)和它的下游信号通路ras-Raf-MEK-ERK,PI3K/Akt和核因子κB(NF-κB)通路有重要关系.其中PI3K/Akt通路除了其潜在的促生长能力外,它的抗凋亡作用和肿瘤细胞对广谱凋亡刺激的抵抗性有密切关系.因此,PI3K/Akt通路可能是胰腺癌分子靶向治疗的一个潜在新靶点.     

大肠癌组织bFGF,PKB,Cyclin A的表达及其与临床的相关性

目的:研究大肠癌组织中碱性成纤维细胞生长因子(bFGF),蛋白激酶B(PKB)及细胞周期蛋白A(Cvclin A)mRNA的表达水平及与临床病理的关系.方法:采用TRIzol法分别提取60例大肠癌组织,癌旁组织和10例正常组织的RNA,应用RT-PCR方法检测bFGF,PKB,Cyclin A mRNA的表达水平,PCR产物经凝胶成像及分析系统扫描后,以β-actin为参照标化bFGF,PKB,Cvclin A的含量.通过统计学分析其与临床病理关系.结果:bFGF,PKB,Cyclin A在大肠癌组织中的表达与癌旁组织相比有显著差异(bFGF:60%vs 10%;PKB:55% vs 35%;CyclinA:70% vs 5%;all P＜0.05),其表达水平与大肠癌Dukes分期有关(bFGF:χ2=4.434,P＜0.05;PKB:χ2=13.549,P＜0.01;CyclinA:χ2=21.210,P＜0.01).PKB在低分化肿瘤中的表达阳性率高于中高分化肿瘤(14/14 vs 29/46,P＜0.05).Cyclin A的表达在高、中分化肿瘤中明显高于低分化肿瘤(37/46 vs 3/14,P＜0.05).结论:bFGF,PKB,Cyclin A的mRNA水平与大肠癌的发生、发展相关.     

PTEN/AKT在子宫内膜癌中的表达及临床意义

目的研究抑癌基因PTEN在子宫内膜癌中的表达及其与蛋白激酶B（PKB/AKT）表达。方法采用RT-PCR及Western印迹杂交法检测30例子宫内膜癌、20例非典型增生、20例正常子宫内膜组织中PTEN、AKTmRNA及蛋白的表达。结果子宫内膜癌组织中PTEN的表达低于非典型增生和正常子宫内膜组织（P〈0.01）;子宫内膜癌组织中AKT表达明显高于非典型增生和正常子宫内膜组织（P〈0.01）。结论子宫内膜癌组织中AKT的表达水平的明显增高,是由于PTEN表达下调或缺失而引起,AKT在子宫内膜癌的发生中起着重要的作用。     

PI3K/Akt和COX-2信号通路阻断在胃癌治疗中的应用

磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/PKB,PI3K/Akt)和环氧合酶-2(COX-2)信号通路的异常改变在肿瘤的发生、发展过程中起重要作用. 并且可以引起肿瘤的一系列生物学行为改变, 对肿瘤患者的治疗和预后产生很大影响. 本文研究PI3K/Akt和COX-2信号通路阻断及其机制, 为包括胃癌在内的多种肿瘤的分子靶向治疗提供新的方向.     

mTOR信号通路与胃癌的相关性研究

正哺乳动物雷帕霉素靶蛋白(mTOR)属于丝氨酸/苏氨酸蛋白激酶的一种,其自酵母中分离出来,在P13K/AKT/mTOR信号通路中是蛋白激酶B(Akt)的下游底物。mTOR是一种含有2549个氨基酸残基的蛋白质分子,生理状态下,该蛋白在各种刺激因子的作用下发挥调控细胞周期、细胞生长增殖等作用,因此mTOR在多种肿瘤组织中表达异     

新的抗肿瘤靶点Akt与胰腺癌分子靶向治疗

Akt／PKB是一种丝氨酸／苏氨酸蛋白激酶．属于cAMP依赖的蛋白激酶A、蛋白激酶G、蛋白激酶C（AGC）超家族．它是P13K/Akt通路中的关键分子．通过磷酸化mTOR、Bad、GSK3、mdm2、caspase家族、Forkhead家族等多种作用底物．在促进肿瘤细胞的生长、增殖．抑制细胞凋亡．促使细胞侵袭和转移．促进血管生成．抵抗化疗和放疗中细胞的凋亡等方面起重要作用。最近在许多人类肿瘤中发现．PKB／Akt信号通路异常与肿瘤发生、发展关系密切．     

ACTH inhibits A Ras-dependent anti-apoptotic and mitogenic pathway in mouse Y1 adrenocortical cells

Mouse Y1 adrenocortical tumor cells harbor amplified and overexpressed c-Ki-ras gene, displaying relatively high constitutive levels of Ras x GTP. Here we report that Y1 cells also constitutively display high levels of phosphorylated AKT/PKB, that are dependent on Ras x GTP and PI3K. ACTH rapidly causes dephosphorylation of AKT/PKB in a cAMP/PKA dependent maner. This ACTH inhibition of the anti-apoptic and mitogenic AKT/PKB pathway is likely to be relevant in ACTH growth inhibitory effects in Y-adrenocortical cells.     

Macrophage inflammatory protein 1-alpha (MIP-1 alpha ) triggers migration and signaling cascades mediating survival and proliferation in multiple myeloma (MM) cells

Recently, it has been demonstrated that macrophage inflammatory protein 1- alpha (MIP-1 alpha) is crucially involved in the development of osteolytic bone lesions in multiple myeloma (MM). The current study was designed to determine the direct effects of MIP-1 alpha on MM cells. Thus, we were able to demonstrate that MIP-1 alpha acts as a potent growth, survival, and chemotactic factor in MM cells. MIP-1 alpha-induced signaling involved activation of the AKT/protein kinase B (PKB) and the mitogen-activated protein kinase (MAPK) pathway. In addition, inhibition of AKT activation by phosphatidylinositol 3- kinase (PI3-K) inhibitors did not influence MAPK activation, suggesting that there is no cross talk between MIP-1 alpha-dependent activation of the PI3-K/AKT and extracellular-regulated kinase (ERK) pathway. Our data suggest that besides its role in development of osteolytic bone destruction, MIP-1 alpha also directly affects cell signaling pathways mediating growth, survival, and migration in MM cells and provide evidence that MIP-1 alpha might play a pivotal role in the pathogenesis of MM.     

Novel protein kinases in pancreatic cell growth and cancer

The network of enzymes that contribute to the signal transduction of extracellular factors in pancreatic cancer is ever increasing. The classical Raf-MEK-ERK signaling cascade plays a crucial role in the regulation of apoptosis, proliferation, and metastasis of pancreatic cancer. Phosphatidylinositide-3-kinase also contributes to growth and prevents apoptosis in pancreatic cancer cells, acting in part via its downstream targets, PKB/AKT and the FRAP/p70s6k signaling complex. Recently, members of the PKC family of serine threonine kinases have emerged as novel modulators of transformation and cell cycle progression of pancreatic cancers. The novel PKD family of serine threonine kinases has just been detected in pancreatic cancer and awaits its functional characterization in these tumors.     

Asymmetric cancer cell division regulated by AKT

Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with small-molecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.     

AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation

AKT serine threonine kinase of the protein kinase B (PKB) family plays essential roles in cell survival, growth, metabolism, and differentiation. In the erythroid system, AKT is known to be rapidly phosphorylated and activated in response to erythropoietin (Epo) engagement of Epo receptor (EpoR) and to sustain survival signals in cultured erythroid cells. Here we demonstrate that activated AKT complements EpoR signaling and supports erythroid-cell differentiation in wild-type and JAK2-deficient fetal liver cells. We show that erythroid maturation of AKT-transduced cells is not solely dependent on AKT-induced cell survival or proliferation signals, suggesting that AKT transduces also a differentiation-specific signal downstream of EpoR in erythroid cells. Down-regulation of expression of AKT kinase by RNA interference, or AKT activity by expression of dominant negative forms, inhibits significantly fetal liver-derived erythroid-cell colony formation and gene expression, demonstrating that AKT is required for Epo regulation of erythroid-cell maturation.     

AKT signalling in the failing heart

AKT is a serine/threonine protein kinase, also known as protein kinase B, which regulates cardiac growth, myocardial angiogenesis, glucose metabolism, and cell death in cardiac myocytes. AKT is activated by its phosphorylation at Thr 308 and ser 473 by PDK1 and mTORC2, respectively, in response to trophic stimuli such as insulin and insulin growth factor. c-Jun N-Terminal Kinases (JNKs) phosphorylate AKT at Thr 450 and potentiate its interaction with its downstream effectors. The short-term activation of AKT promotes physiological hypertrophy and protection from myocardial injury; whereas, its long-term activation causes pathological hypertrophy and heart failure. In this review we will discuss the role of AKT in regulating signalling pathways in the heart with special emphasis on the role of AKT in modulating stress induced autophagic cell death in cardiomyocytes in vitro.     

The involvement of phosphatidylinositol 3-kinase in gonadotropin-releasing hormone-induced gonadotropin alpha- and FSHbeta-subunit genes expression in clonal gonadotroph LbetaT2 cells

Akt/protein kinase B (Akt/PKB), which is activated by phosphatidylinositol-3 kinase (PI3-kinase), plays an important role in cell survival and cell proliferation. Using the well differentiated, clonal gonadotroph cell line, LbetaT2, we examined (1) whether Akt/PKB was activated by gonadotropin-releasing hormone (GnRH); (2) the contribution of PI3-kinase-Akt/PKB pathway in each of gonadotropin subunit gene expression; (3) crosstalk between extracellular signal-regulated kinase (ERK) and Akt/PKB pathways. Insulin-like growth factor-1 (IGF-1) was used as Akt/PKBs classic activator. Western blot analyses using antibodies specific for the phosphorylated forms of ERK and Akt/PKB demonstrated that both were rapidly phosphorylated following treatment with GnRH and IGF-1. Akt/PKB activation by GnRH and IGF-1 was completely eliminated in the presence of the PI3-kinase inhibitor, LY 294002, but not in the presence of an Akt/PKB inhibitor. Interestingly, the total amount of Akt/PKB protein was dramatically increased in the presence of LY 294002. Phosphorylation of ERK was significantly increased in the presence of LY 294002 alone, and was further increased when GnRH was used in combination with LY 294002. In experiments using a luciferase reporter construct containing the serum response element (SRE), a known target of the ERK pathway, LY 294002 but not the Akt/PKB inhibitor increased SRE-luciferase activity. GnRH-induced SRE-luciferase activity was significantly increased by LY 294002. GnRH stimulation resulted in gonadotropin LHbeta, FSHbeta, and alpha-subunit promoter activation, while IGF-1 failed to stimulate any of them. GnRH-induced gonadotropin promoter activities were not modulated in the presence of an Akt/PKB inhibitor, but treatment with LY 294002 or Wortmannin resulted in a significant increase in alpha- and FSHbeta-subunit promoter activation, both with and without GnRH. LY 294002, but not the Akt/PKB inhibitor, significantly inhibited cell proliferation. These results suggest that GnRH-induced gonadotropin gene expression is not regulated through the Akt/PKB pathway; however, PI3-kinase may be involved in the negative regulation of alpha- and FSHbeta-subunit gene expression as well as cell proliferation.