V-akt Murine Thymoma Viral Oncogene Research Articles

Kif13b Regulates PNS and CNS Myelination through the Dlg1 Scaffold.

Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.

A common variation of the PTEN gene is associated with peripheral insulin resistance

AimPhosphatase and tensin homologue (PTEN) reduces insulin sensitivity by inhibiting the phosphatidylinositol 3-kinase (PI3K)/v-akt murine thymoma viral oncogene homologue (Akt) pathway. This study investigated how a common single nucleotide polymorphism near PTEN, previously associated with fasting levels of plasma insulin and glucose, influences in vivo glucose metabolism and insulin signalling. The primary outcome measure was the gene variant's association with peripheral glucose disposal rate and, secondarily, whether this association was explained by altered activities of PTEN targets PI3K and Akt. MethodsA total of 183 normoglycaemic Danes, including 158 twins and 25 singletons, were genotyped for PTEN rs11202614, which is in complete linkage disequilibrium with rs2142136 and rs10788575, which have also been reported in association with glycaemic traits and type 2 diabetes (T2D). Hepatic and peripheral insulin sensitivity was measured using tracer and euglycaemic–hyperinsulinaemic clamp techniques; insulin secretion was assessed by intravenous glucose tolerance test; and muscle biopsies were taken during insulin infusion from 150 twins for measurement of PI3K and Akt activities. ResultsThe minor G allele of PTEN rs11202614 was associated with elevated fasting plasma insulin levels and a decreased peripheral glucose disposal rate, but not with the hepatic insulin resistance index or insulin secretion measured as the first-phase insulin response and disposition index. The single nucleotide polymorphism was not associated with either PI3K or Akt activities. ConclusionA common PTEN variation is associated with peripheral insulin resistance and subsequent risk of developing T2D. However, the association with insulin resistance is not explained by decreased proximal insulin signalling in skeletal muscle.

Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response.

The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.

Expression of cardiac insulin signalling genes and proteins in rats fed a high-sucrose diet: effect of bilberry anthocyanin extract

ScopeInsulin resistance is associated with impaired cardiac function, but the underlying molecular abnormalities are largely unexplained. Bilberry anthocyanin (BAcn) may be protective, as it appears to potentiate insulin action.MethodsRats were randomly allocated to control, sucrose-fed (SF) or sucrose-fed + BAcn diets (SF-A) for 15 weeks. Cardiac insulin signalling genes and proteins were quantified using reverse transcription quantitative real-time polymerase chain reaction and western blots.ResultsGlucose tolerance was not different with treatment. SF showed lower (p < 0.05) ferric reducing antioxidant power, which increased with BAcn. SF resulted in significantly decreased (p < 0.05) expression of 10 genes: acetyl-coenzyme A carboxylase alpha; V-Akt murine thymoma viral oncogene homolog 1; Bcl2-like 1; cytosine-cytosine-adenosine-adenosine-thymidine/enhancer binding protein; FK506 binding protein 12-rapamycin associated; glycerol-3-phosphate dehydrogenase 1 (soluble); solute carrier family 2 (facilitated glucose transporter), member 1, 4; hexokinase 2; and thyroglobulin. SF-A prevented these changes. Compared to SF-A, SF up-regulated (p < 0.05) complement factor D and phosphoinositide-3-kinase, regulatory subunit1 (α); sterol regulatory element binding transcription factor 1 was down-regulated (p < 0.05). SF increased (p < 0.05) cardiac phospholamban and decreased phosphorylated troponin I, which were not attenuated by BAcn. Compared to control or SF, SF-A resulted in significantly lower (p < 0.05) 5′-AMP-activated protein kinase.ConclusionsSF lowered antioxidant capacity and changed the expression of insulin signalling genes, which were modulated by BAcn.

METTL13 is downregulated in bladder carcinoma and suppresses cell proliferation, migration and invasion.

The incidence of bladder cancer has increased in the last few decades, thus novel markers for early diagnosis and more efficacious treatment are urgently needed. It found that METTTL13 protein is aberrant expression in variety of human cancers and METTL13 was involved in oncogenic pathways. However, the role of METTL13 has been unexplored in bladder cancer to date. Here, expression of METTL13 was lower in bladder cancer tissue samples and cancer cell lines than in normal bladder tissue and cell lines. METTL13 was downregulated in the late stages of the disease and was maintained at low level throughout the tumor progression process based on tumor node metastasis (TNM) staging. Further research suggested that METTL13 negatively regulates cell proliferation in bladder cancer and reinstates G1/S checkpoint via the coordinated downregulation of CDK6, CDK4 and CCND1, decreased phosphorylation of Rb and subsequent delayed cell cycle progression. Moreover, METTL13-dependent inhibition of bladder cancer cell migration and invasion is mediated by downregulation of FAK (Focal adhesion kinase) phosphorylation, AKT (v-akt murine thymoma viral oncogene) phosphorylation, β-catenin expression and MMP-9 expression. These integrated efforts have identified METTL13 as a tumor suppressor and might provide promising approaches for bladder cancer treatment and prevention.

AKT Inhibition Promotes Nonautonomous Cancer Cell Survival.

Small molecule inhibitors of AKT (v-akt murine thymoma viral oncogene homolog) signaling are being evaluated in patients with various cancer types, but have so far proven therapeutically disappointing for reasons that remain unclear. Here, we treat cancer cells with subtherapeutic doses of Akti-1/2, an allosteric small molecule AKT inhibitor, in order to experimentally model pharmacologic inhibition of AKT signaling in vitro. We then apply a combined RNA, protein, and metabolite profiling approach to develop an integrated, multiscale, molecular snapshot of this "AKT(low)" cancer cell state. We find that AKT-inhibited cancer cells suppress thousands of mRNA transcripts, and proteins related to the cell cycle, ribosome, and protein translation. Surprisingly, however, these AKT-inhibited cells simultaneously upregulate a host of other proteins and metabolites posttranscriptionally, reflecting activation of their endo-vesiculo-membrane system, secretion of inflammatory proteins, and elaboration of extracellular microvesicles. Importantly, these microvesicles enable rapidly proliferating cancer cells of various types to better withstand different stress conditions, including serum deprivation, hypoxia, or cytotoxic chemotherapy in vitro and xenografting in vivo. These findings suggest a model whereby cancer cells experiencing a partial inhibition of AKT signaling may actually promote the survival of neighbors through non-cell autonomous communication.

Transcriptomic differences of genes in the avian target of rapamycin (avTOR) pathway in a divergent line of meat-type chickens selected for feed efficiency.

Avian target of rapamycin (avTOR) is a highly conserved serine-threonine kinase that serves as an intracellular energy and nutrient sensor and regulates cell division, growth, and apoptosis. The role of avTOR in mediating feed intake and growth in poultry is unknown. We studied avTOR signaling activities in duodenum and liver tissues at days 35 and 42 in chickens divergently selected for low (LRFI) or high (HRFI) residual feed intake. The differential expression of genes involved in the avTOR pathway was assayed using real-time polymerase chain reaction. In the duodenum, avTOR was up-regulated in the LRFI chickens at both time points as compared with the HRFI chickens. Other genes found to be differentially expressed at day 35 included v-akt murine thymoma viral oncogene homolog, eukaryotic translation elongation factor 2, eukaryotic translation initiation factor 4E binding protein 1, 3-phosphoinositide dependent protein kinase-1, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KP1), avTOR associated protein, LST8 homolog, ghrelin, phosphoinositide-3-kinase (PI3K), forkhead box O1, and p53 E3 ubiquitin protein ligase homolog (MDM2). At day 42, there was no change in the expression of the avTOR target RPS6KP1 or MDM2. In the liver, changes in the expression of components of the avTOR pathway primarily occurred at day 42, and differential gene expression suggests that avTOR complex 1 (avTORC1) affects feed efficiency at day 42. avTORC1 may be activated in the duodenum of feed-efficient birds to increase nutrient mobilization to other peripheral tissues. Furthermore, activation of avTOR in relation to feed efficiency may be tissue specific and may depend on the tissue's need for growth and nutrient transport. Genetic markers in key genes involved in the avTOR/PI3K pathway could be developed to improve feed efficiency in meat-type chickens.

Tumor suppressor RIZ1 in obesity and the PI3K/AKT/mTOR pathway.

The aim of this study was to investigate the shared molecular pathways of obesity and cancer by exploring the role of RIZ1 in obesity and the phospatidylinositol 3-kinase (PI3K)/V-Akt murine thymoma viral oncogene homolog (PKB) (AKT)/mechanistic target of rapamycin (mTOR) pathway. Male wild type (WT) and Riz1(-/-) mice (KO) were fed a standard diet (STD) or a high-fat (HF) diet for up to 8 months. These mice were studied for phenotypic and molecular changes. Riz1(-/-) mice gained more weight on a HF diet compared to WT mice, with higher free fatty acid and increased visceral fat. Metabolic cage analysis of Riz1(-/-) mice showed lower oxygen consumption but no changes in food intake and ambulatory activity. Riz1(-/-) mice showed impaired glucose regulation but no change in insulin sensitivity. RNA-seq and quantitative RT-PCR analysis found altered expression in certain glycolysis and ATP production genes such as Ubiad1, Atp5g2, and Cyp4a12. The PI3K/AKT/mTOR pathway was activated in the Riz1(-/-) mice fed a HF diet with higher Akt3 mRNA levels and increased phosphorylation of AKT (Ser473), mTOR, and S6. The results identify RIZ1 as an important regulator of both Akt3 transcription and AKT phosphorylation and suggest a role for RIZ1 in HF-induced obesity and the AKT pathway.

Transducer of ERBB2.1 (TOB1) as a Tumor Suppressor: A Mechanistic Perspective

Transducer of ERBB2.1 (TOB1) is a tumor-suppressor protein, which functions as a negative regulator of the receptor tyrosine-kinase ERBB2. As most of the other tumor suppressor proteins, TOB1 is inactivated in many human cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves mRNA deadenylation and is associated with the reduction of both cyclin D1 and cyclin-dependent kinase (CDK) expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-catenin, and inhibits β-catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine thymoma viral oncogene (AKT) signaling and induces cancer cell apoptosis by activating BCL2-associated X (BAX) protein and inhibiting the BCL-2 and BCL-XL expressions. The tumor-specific overexpression of TOB1 results in the activation of other tumor suppressor proteins, such as mothers against decapentaplegic homolog 4 (SMAD4) and phosphatase and tensin homolog-10 (PTEN), and blocks tumor progression. TOB1-overexpressing cancer cells have limited potential of growing as xenograft tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1 tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways.

A20 Inhibits β-Cell Apoptosis by Multiple Mechanisms and Predicts Residual β-Cell Function in Type 1 Diabetes

Activation of the transcription factor nuclear factor kappa B (NFkB) contributes to β-cell death in type 1 diabetes (T1D). Genome-wide association studies have identified the gene TNF-induced protein 3 (TNFAIP3), encoding for the zinc finger protein A20, as a susceptibility locus for T1D. A20 restricts NF-κB signaling and has strong antiapoptotic activities in β-cells. Although the role of A20 on NF-κB inhibition is well characterized, its other antiapoptotic functions are largely unknown. By studying INS-1E cells and rat dispersed islet cells knocked down or overexpressing A20 and islets isolated from the β-cell-specific A20 knockout mice, we presently demonstrate that A20 has broader effects in β-cells that are not restricted to inhibition of NF-κB. These involves, suppression of the proapoptotic mitogen-activated protein kinase c-Jun N-terminal kinase (JNK), activation of survival signaling via v-akt murine thymoma viral oncogene homolog (Akt) and consequently inhibition of the intrinsic apoptotic pathway. Finally, in a cohort of T1D children, we observed that the risk allele of the rs2327832 single nucleotide polymorphism of TNFAIP3 predicted lower C-peptide and higher hemoglobin A1c (HbA1c) levels 12 months after disease onset, indicating reduced residual β-cell function and impaired glycemic control. In conclusion, our results indicate a critical role for A20 in the regulation of β-cell survival and unveil novel mechanisms by which A20 controls β-cell fate. Moreover, we identify the single nucleotide polymorphism rs2327832 of TNFAIP3 as a possible prognostic marker for diabetes outcome in children with T1D.

Revealing the role of VEGFA in clear cell sarcoma of the kidney by protein-protein interaction network and significant pathway analysis.

Despite clear cell sarcoma of the kidney (CCSK) being the second most common renal tumor in children, its mechanism has not yet been fully investigated. The aim of the present study was to investigate the potential role of vascular endothelial growth factor A (VEGFA) in CCSK development. Following preprocessing of the original GSE2712 data, the differentially-expressed genes (DEGs) between 14 CCSK and 3 fetal kidney samples were identified through Significance Analysis of Microarrays, using the R package. Pathway enrichment analysis was then performed on the DEGs. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins database and the DEGs that were enriched in the most significant pathways. Following this, gene ontology analysis was performed on the VEGFA-associated genes, whilst transcription factor binding site analysis was conducted on the hot genes. A total of 2,681 DEGs, including 543 upregulated and 2,138 downregulated genes, were identified, and these were significantly enriched in pathways associated with cancer and focal adhesion. Furthermore, VEGFA, integrin β1, integrin αV, v-akt murine thymoma viral oncogene homolog 1 and endothelial growth factor receptor were identified as hot genes in the PPI network. In addition, the upregulated VEGFA-associated genes, cyclin D1 and cyclin-dependent kinase inhibitor 1B, affected kinase regulation, and the downregulated VEGFA-associated genes, receptor tyrosine-protein kinase erbB-2, mesenchymal-epithelial transition tyrosine kinase receptor and kinase insert domain receptor, were enriched in the protein tyrosine kinase process. It was identified that VEGFA was regulated by restorer of fertility, erythromycin resistance methylase, GA binding protein subunit α, norepinephrine transporter, nuclear factor κB and Sp2 transcription factor genes. Overall, VEGFA and its associated genes serve important roles during CCSK development, and alongside transcription factors, they may function as novel therapeutic targets for disease treatment.

MiR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7.

The cytokine transforming growth factor (TGF)-β1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-β1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-β1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN.

Analysis of differentially expressed genes between endometrial carcinosarcomas and endometrioid endometrial carcinoma by bioinformatics.

This study aimed to explore the underlying molecular mechanisms of endometrial carcinosarcomas (ECS) and endometrioid endometrial carcinoma (EEC) by bioinformatics analysis. Gene expression profile GSE33723 was downloaded from the Gene Expression Omnibus. A total of 15 ECS and 23 EEC samples were used to identify the differentially expressed genes (DEGs) by significance analysis of microarrays. After construction of protein-protein interaction (PPI) network, Gene Ontology (GO) functional and pathway enrichment analyses of DEGs were performed, followed by network module analysis. A total of 49 DEGs were identified between EEC and ECS samples. In the PPI network, TP53 (tumor protein p53) was selected as the highest degree, hub centrality and betweenness. The top 10 enriched GO terms including regulation of cell death and top 10 significant pathways including cell cycle were selected. After network module analysis, PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1) and AKT2 (v-akt murine thymoma viral oncogene homolog 2) were selected as the co-expressed genes in the states of ECS while STAT3 (signal transducer and activator of transcription 3) and JAZF (JAZF zinc finger 1) were selected as the co-expressed genes in the states of EEC. The DEGs, such as TP53, PIK3R1 and AKT2 may be used for targeted diagnosis and treatment of ECS while STAT3 and JAZF1 may be served as a target for EEC.

Introducing differential expression of human heat shock protein 27 in hepatocellular carcinoma: moving toward identification of cancer biomarker.

Previously, it has to be acknowledged that overexpressed heat shock protein B27 (HSPB27) have been implicated in the etiology of wide range of human cancers. However, the molecular mechanism leading to the disease initiation to progression in liver cancer is still unknown. Present work was undertaken to investigate the differentially expressed HSPB27 in association with those damages that lead to liver cancer development. For the identification of liver cancer biomarker, samples were subjected to comparative proteomic analysis using two-dimensional gel electrophoresis (2-DE) and were further validated by Western blot and immunohistochemical analysis. After validation, in silico studies were applied to demonstrate the significantly induced phosphorylated and S-nitrosylated signals. The later included the interacting partner of HSPB27, i.e., mitogen-activated protein kinase-3 and 5 (MAPK3 and 5), ubiquitin C (UBC), v-akt murine thymoma viral oncogene homolog 1 (AKT1), mitogen-activated protein kinase 14 (MAPK14), and tumor protein p53 (TP53), which bestowed with critical capabilities, namely, apoptosis, cell cycling, stress activation, tumor suppression, cell survival, angiogenesis, proliferation, and stress resistance. Taking together, these results shed new light on the potential biomarker HSPB27 that overexpression of HSPB27 did lead to upregulation of their interacting partner that together demonstrate their possible role as a novel tumor progressive agent for the treatment of metastasis in liver cancer. HSPB27 is a promising diagnostic marker for liver cancer although further large-scale studies are required. Also, molecular profiling may help pave the road to the discovery of new therapies.

LTβR signalling preferentially accelerates oncogenic AKT-initiated liver tumours.

ObjectivesThe relative contributions of inflammatory signalling and sequential oncogenic dysregulation driving liver cancer pathogenesis remain incompletely understood. Lymphotoxin-β receptor (LTβR) signalling is critically involved in hepatitis and liver tumorigenesis. Therefore, we explored the interdependence of inflammatory lymphotoxin signalling and specific oncogenic pathways in the progression of hepatic cancer.DesignPathologically distinct liver tumours were initiated by hydrodynamic transfection of oncogenic V-Akt Murine Thymoma Viral Oncogene Homolog 1 (AKT)/β-catenin or AKT/Notch expressing plasmids. To investigate the relationship of LTβR signalling and specific oncogenic pathways, LTβR antagonist (LTβR-Fc) or agonist (anti-LTβR) were administered post oncogene transfection. Initiated livers/tumours were investigated for changes in oncogene expression, tumour proliferation, progression, latency and pathology. Moreover, specific LTβR-mediated molecular events were investigated in human liver cancer cell lines and through transcriptional analyses of samples from patients with intrahepatic cholangiocarcinoma (ICC).ResultsAKT/β-catenin-transfected livers displayed increased expression of LTβ and LTβR, with antagonism of LTβR signalling reducing tumour progression and enhancing survival. Conversely, enforced LTβR-activation of AKT/β-catenin-initiated tumours induced robust increases in proliferation and progression of hepatic tumour phenotypes in an AKT-dependent manner. LTβR-activation also rapidly accelerated ICC progression initiated by AKT/Notch, but not Notch alone. Moreover, LTβR-accelerated development coincides with increases of Notch, Hes1, c-MYC, pAKT and β-catenin. We further demonstrate LTβR signalling in human liver cancer cell lines to be a regulator of Notch, pAKTser473 and β-catenin. Transcriptome analysis of samples from patients with ICC links increased LTβR network expression with poor patient survival, increased Notch1 expression and Notch and AKT/PI3K signalling.ConclusionsOur findings link LTβR and oncogenic AKT signalling in the development of ICC.

Association between Polymorphisms of the AKT1 Gene Promoter and Risk of the Alzheimer's Disease in a Chinese Han Population with Type 2 Diabetes.

Alzheimer's disease (AD) is a multifactor disease that has been reported to have a close association with type 2 diabetes (T2D) where the v-akt murine thymoma viral oncogene homolog 1 (AKT1) plays an important role in the protein synthesis pathways and cell apoptosis processes. Evidence has been shown that AKT1 protein may be related to AD risk among patients with T2D. The aim of this study was to analyze the potential association between single nucleotide polymorphisms of AKT1 promoter and the risk of AD among patients with T2D. The association between AKT1 polymorphisms and AD risk in patients with T2D was assessed among 574 consecutive unrelated subjects including 112 AD patients with T2D, 231 patients with AD, and 231 healthy controls in a case-control study. The cognitive function of all subjects was assessed using MMSE. Six single nucleotide polymorphisms with minor allele frequency >0.2 (rs2498786, rs74090038, rs2494750, rs2494751, rs5811155, and rs2494752) in AKT1 promoter were analyzed by polymerase chain reaction (PCR), and the concentration of AKT1 protein in serum was tested using enzyme-linked immunosorbent assay (ELISA). Overall, there was statistically significant difference in AKT1 rs2498786 polymorphism. The CC frequency of AKT1 rs2498786 polymorphism in AD with T2D group and AD control group was significantly higher than that in healthy control group (PAD+T2D vs. health < 0.0001, PAD vs. health < 0.0001). However, the difference was not found between AD with T2D group and AD control group. Compared with healthy control group, the plasma levels of AKT1 protein in AD with T2D group (PAD+T2D vs. health < 0.0001) and AD control group (PAD vs. health = 0.0003) decreased significantly. Among genotypes of AKT1 rs2498786 polymorphism, the AKT1 protein level in GG genotype was significantly higher than that in GC genotype (PGG vs. GC < 0.0001) and CC genotype (PGG vs. CC < 0.0001). The study suggests that AKT1 rs2498786 polymorphism in insulin signaling pathway may be associated with AD risk and different genotypes may affects levels of protein expression. However, the polymorphism is not shown to be exclusive in AD patients with T2D.

Glucose-dependent acetylation of Rictor promotes targeted cancer therapy resistance

Cancer cells adapt their signaling in response to nutrient availability. To uncover the mechanisms regulating this process and its functional consequences, we interrogated cell lines, mouse tumor models, and clinical samples of glioblastoma (GBM), the highly lethal brain cancer. We discovered that glucose or acetate is required for epidermal growth factor receptor vIII (EGFRvIII), the most common growth factor receptor mutation in GBM, to activate mechanistic target of rapamycin complex 2 (mTORC2) and promote tumor growth. Glucose or acetate promoted growth factor receptor signaling through acetyl-CoA-dependent acetylation of Rictor, a core component of the mTORC2 signaling complex. Remarkably, in the presence of elevated glucose levels, Rictor acetylation is maintained to form an autoactivation loop of mTORC2 even when the upstream components of the growth factor receptor signaling pathway are no longer active, thus rendering GBMs resistant to EGFR-, PI3K (phosphoinositide 3-kinase)-, or AKT (v-akt murine thymoma viral oncogene homolog)-targeted therapies. These results demonstrate that elevated nutrient levels can drive resistance to targeted cancer treatments and nominate mTORC2 as a central node for integrating growth factor signaling with nutrient availability in GBM.

The androgen receptor as an emerging target in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the male-dominant liver diseases with poor prognosis, although treatments for HCC have been progressing in the past decades. Androgen receptor (AR) is a member of the nuclear receptor superfamily. Previous studies reported that AR was expressed in human HCC and non-HCC tissues. AR is activated both ligand-dependently and ligand-independently. The latter is associated with a mitogen-activated protein kinase–, v-akt murine thymoma viral oncogene homolog 1–, or signal-transducer and activator of transcription–signaling pathway, which has been implicated in the development of HCC. It has been reported that more than 200 RNA expression levels are altered by androgen treatment. In the liver, androgen-responsive genes are cytochrome P450s, transforming growth factor β, vascular endothelial growth factor, and glucose-regulated protein 78 kDa, which are also associated with human hepatocarcinogenesis. Recent studies also revealed that AR plays a role in cell migration and metastasis. It is possible that cross-talk among AR-signaling, endoplasmic reticulum stress, and innate immune response is important for human hepatocarcinogenesis and HCC development. This review shows that AR could play a potential role in human HCC and represent one of the important target molecules for the treatment of HCC.

Mutations in the PP2A regulatory subunit B family genes PPP2R5B, PPP2R5C and PPP2R5D cause human overgrowth.

Overgrowth syndromes comprise a group of heterogeneous disorders characterised by excessive growth parameters, often in association with intellectual disability. To identify new causes of human overgrowth, we have been undertaking trio-based exome sequencing studies in overgrowth patients and their unaffected parents. Prioritisation of functionally relevant genes with multiple unique de novo mutations revealed four mutations in protein phosphatase 2A (PP2A) regulatory subunit B family genes protein phosphatase 2, regulatory Subunit B’, beta (PPP2R5B); protein phosphatase 2, regulatory Subunit B’, gamma (PPP2R5C); and protein phosphatase 2, regulatory Subunit B’, delta (PPP2R5D). This observation in 3 related genes in 111 individuals with a similar phenotype is greatly in excess of the expected number, as determined from gene-specific de novo mutation rates (P = 1.43 × 10−10). Analysis of exome-sequencing data from a follow-up series of overgrowth probands identified a further pathogenic mutation, bringing the total number of affected individuals to 5. Heterozygotes shared similar phenotypic features including increased height, increased head circumference and intellectual disability. The mutations clustered within a region of nine amino acid residues in the aligned protein sequences (P = 1.6 × 10−5). We mapped the mutations onto the crystal structure of the PP2A holoenzyme complex to predict their molecular and functional consequences. These studies suggest that the mutations may affect substrate binding, thus perturbing the ability of PP2A to dephosphorylate particular protein substrates. PP2A is a major negative regulator of v-akt murine thymoma viral oncogene homolog 1 (AKT). Thus, our data further expand the list of genes encoding components of the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signalling cascade that are disrupted in human overgrowth conditions.

Protective Effects of Liraglutide and Linagliptin in C. elegans as a New Model for Glucose-Induced Neurodegeneration.

Liraglutide and linagliptin are novel drugs for the treatment of diabetes. Antioxidative and neuroprotective effects have been described for both compounds. However, it is not yet known, whether these mechanisms are also protective against diabetic retinal neurodegeneration. We assessed the antioxidative and neuroprotective capabilities of liraglutide and linagliptin as well as the signaling pathways involved, by using C. elegans as a model for glucose-induced neurodegeneration. C. elegans were cultivated under conditions, which mimic clinical hyperglycemia, and treated with 160 μmol/l liraglutide or 13 μmol/l linagliptin. Oxidative stress was reduced by 29 or 78% and methylglyoxal-derived advanced glycation endproducts (AGEs) by 33 or 22%, respectively. This resulted in an improved neuronal function by 42 or 60% and an extended mean lifespan by 9 or 11%, respectively. Antioxidative and AGE reducing effects of liraglutide and linagliptin were not dependent on v-akt murine thymoma viral oncogene homologue 1/forkhead box O1 (AKT1/FOXO). Neuroprotection by liraglutide was AKT1/FOXO dependent, yet AKT1/FOXO independent upon linagliptin treatment. Both liraglutide and linagliptin exert neuroprotective effects in an experimental model for glucose-induced neurodegeneration, however, the signaling pathways differ in the present study. Further pharmacological intervention with these pathways may help to delay the clinical onset of diabetic retinopathy by preserving neuronal integrity.