BACKGROUND: While hundreds of genes have been implicated already in the etiology of schizophrenia, the exact cause is not known or the disease is considered multigenic in origin. Recent discoveries of new types of RNAs and the gradual elimination of the "junk DNA" hypothesis refocused the attention on the noncoding part of the human genome. Here we re-analyzed a recent dataset of differentially methylated genes from schizophrenic patients and cross-tabulated them with cis regulatory and repetitive elements and microRNAs known to be involved in schizophrenia. RESULTS: We found that the number of schizophrenia-related (SZ) microRNA targets follows a scale-free distribution with several microRNA hubs and that schizophrenia-related microRNAs with shared targets form a small-world network. The top ten microRNAs with the highest number of SZ gene targets regulate approximately 80 % of all microRNA-regulated genes whereas the top two microRNAs regulate 40-52 % of all such genes. We also found that genes that are regulated by the same microRNAs tend to have more protein-protein interactions than randomly selected schizophrenia genes. This highlights the role microRNAs possibly play in coordinating the abundance of interacting proteins, an important function that has not been sufficiently explored before. The analysis revealed that GABBR1 is regulated by both of the top two microRNAs and acts as a hub by interacting with many schizophrenia-related genes and sharing several types of transcription-binding sites with its interactors. We also found that differentially methylated repetitive elements are significantly more methylated in schizophrenia, pointing out their potential role in the disease. CONCLUSIONS: We find that GABBR1 has a central importance in schizophrenia, even if no direct cause and effect have been shown for it for the time. In addition to being a hub in microRNA-derived regulatory pathways and protein-protein interactions, its centrality is also supported by the high number of cis regulatory elements and transcription factor-binding sites that regulate its transcription. These findings are in line with several genome-wide association studies that repeatedly find the major histocompatibility region (where GABBR1 is located) to have the highest number of single nucleotide polymorphisms in schizophrenics. Our model also offers an explanation for the downregulation of protein kinase B, another consistent finding in schizophrenic patients. Our observations support the notion that microRNAs fine-tune the amount of proteins acting in the same biological pathways in schizophrenia, giving further support to the emerging theory of competing endogenous RNAs.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• metylace DNA * MeSH
• mikro RNA genetika   MeSH
• protoonkogenní proteiny c-akt genetika   metabolismus   MeSH
• receptory GABA-B genetika   metabolismus   MeSH
• schizofrenie genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AKT1 protein, human MeSH Prohlížeč
• mikro RNA MeSH
• protoonkogenní proteiny c-akt MeSH
• receptory GABA-B MeSH

Growth factors and hormones activate global and selective protein translation by phosphorylation and therefore activation of p70 S6 kinase through a wortmannin-sensitive phosphoinositide-3 kinase (PI-3K) antiapoptotic pathway and a rapamycin-sensitive signalling pathway of mTOR. Here we demonstrate that the phosphorylation of 40S ribosomal protein S6, a physiological substrate p70 S6 kinase, was highly increased by growth-stimulation of the cytolytic T cells (CTLL2) with interleukin 2 (IL2), which was accompanied with the increased phosphorylation of p70 S6K. The activity of p70 S6K and phosphorylation of the S6 protein was completely blocked by rapamycin and significantly decreased upon treatment of the cells with wortmannin, indicating an involvement of the PI-3K pathway in concert with the signalling pathway of mTOR in IL2-dependent phos-phorylation of ribosomal protein S6. The phosphorylation and activity of PKB/Akt in IL2-stimulated CTLL2 cells were rapamycin-insensitive and reduced upon wortmannin treatment of the cells, confirming a requirement for PI-3K for Akt activity. The data support the hypothesis that Akt may act downstream to PI-3K and upstream to mTOR in an IL2-mediated signal transduction pathway that controls phosphorylation of the regulatory protein S6 in CTLL2 cells.

• MeSH
• androstadieny farmakologie   MeSH
• buněčné linie MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosforylace * MeSH
• imunoblotting MeSH
• inhibitory enzymů farmakologie   MeSH
• interleukin-2 metabolismus   MeSH
• lidé MeSH
• myši MeSH
• protein-serin-threoninkinasy fyziologie   MeSH
• proteinkinasy metabolismus   MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny * MeSH
• ribozomální protein S6 chemie   metabolismus   MeSH
• signální transdukce MeSH
• sirolimus farmakologie   MeSH
• TOR serin-threoninkinasy MeSH
• wortmannin MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AKT1 protein, human MeSH Prohlížeč
• androstadieny MeSH
• inhibitory enzymů MeSH
• interleukin-2 MeSH
• MTOR protein, human MeSH Prohlížeč
• mTOR protein, mouse MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• proteinkinasy MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny * MeSH
• ribozomální protein S6 MeSH
• sirolimus MeSH
• TOR serin-threoninkinasy MeSH
• wortmannin MeSH

The increased phosphorylation and activity of protein kinase B (PKB/Akt) was found early upon butyrate treatment of HT-29 cells with a potent differentiating agent, sodium butyrate. It was accompanied by the increased phosphorylation of glycogen synthase kinase-3 (GSK-3) and the inhibition of the activity of GSK-3beta to catalyze phosphorylation of its substrate, translation initiation factor eIF2B. Phosphorylation of PKB and GSK-3 in HT-29 cells was reduced by wortmannin, the inhibitor of phosphatidylinositol-3' kinase (PI3'-kinase), which is upstream activator of PKB and GSK-3 in the intracellular signalling. Modulation of the activity and phosphorylation of these protein kinases during transient in vitro differentiation of HT-29 cells indicates that control of the PI3'-kinase/PKB-dependent signalling pathway may be implicated very early in the changes of malignant phenotype of HT-29 cells.

• MeSH
• androstadieny farmakologie   MeSH
• buněčná diferenciace MeSH
• buňky HT-29 MeSH
• down regulace MeSH
• enzymová represe MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosforylace MeSH
• inhibitory enzymů farmakologie   MeSH
• kinasa 3 glykogensynthasy MeSH
• kinasy glykogensynthasy MeSH
• lidé MeSH
• nádory tračníku enzymologie   patologie   MeSH
• protein-serin-threoninkinasy * MeSH
• proteinkinasy závislé na vápníku a kalmodulinu metabolismus   MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny antagonisté a inhibitory   metabolismus   MeSH
• signální transdukce MeSH
• wortmannin MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AKT1 protein, human MeSH Prohlížeč
• androstadieny MeSH
• inhibitory enzymů MeSH
• kinasa 3 glykogensynthasy MeSH
• kinasy glykogensynthasy MeSH
• protein-serin-threoninkinasy * MeSH
• proteinkinasy závislé na vápníku a kalmodulinu MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny MeSH
• wortmannin MeSH

In addition to a number of deleterious effects on cellular integrity and functions, diabetic metabolic milieu has been implicated in a rapidly growing number of alterations in signal transduction. In this review we focus on Akt kinase physiology, its alterations in diabetes mellitus (DM), and on the emerging role of this signaling system in the pathophysiology of diabetic microvascular complications. Studies focusing on Akt in diabetes suggest both decrease and increase of Akt activity in DM. Alterations of Akt activity have been found in various tissues and cells in diabetes depending on experimental and clinical contexts. There is convincing evidence suggesting defective Akt signaling in the development of insulin resistance. Similar defects, as in insulin-sensitive tissues, have been reported in endothelia of DM Type 2 models, possibly contributing to the development of endothelial dysfunction under these conditions. In contrast, Akt activity is increased in some tissues and vascular beds affected by complications in DM Type 1. Identification of the role of this phenomenon in DM-induced growth and hemodynamic alterations in affected vascular beds remains one of the major challenges for future research in this area. Future studies should include the evaluation of therapeutical benefits of pharmacological modulators of Akt activity.

• MeSH
• diabetes mellitus 1. typu metabolismus   patofyziologie   MeSH
• diabetes mellitus 2. typu metabolismus   patofyziologie   MeSH
• komplikace diabetu metabolismus   patofyziologie   MeSH
• lidé MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny metabolismus   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• AKT1 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• protoonkogenní proteiny c-akt MeSH
• protoonkogenní proteiny MeSH

Phosphoinositide 3-kinases (PI3K) and phosphoinositide 3-kinase-related protein kinases (PIKK) are two structurally related families of kinases that play vital roles in cell growth and DNA damage repair. Dysfunction of PIKK members and aberrant stimulation of the PI3K/AKT/mTOR signalling pathway are linked to a plethora of diseases including cancer. In recent decades, numerous inhibitors related to the PI3K/AKT/mTOR signalling have made great strides in cancer treatment, like copanlisib and sirolimus. Notably, most of the PIKK inhibitors (such as VX-970 and M3814) related to DNA damage response have also shown good efficacy in clinical trials. However, these drugs still require a suitable combination therapy to overcome drug resistance or improve antitumor activity. Based on the aforementioned facts, we summarised the efficacy of PIKK, PI3K, and AKT inhibitors in the therapy of human malignancies and the resistance mechanisms of targeted therapy, in order to provide deeper insights into cancer treatment.

• Klíčová slova
• AKT, PI3K, PIKK, anticancer therapy, inhibitors,
• MeSH
• 1-fosfatidylinositol-3-kinasa * metabolismus   terapeutické užití   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• inhibitory fosfoinositid-3-kinasy farmakologie   MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádory * farmakoterapie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• TOR serin-threoninkinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• 1-fosfatidylinositol-3-kinasa * MeSH
• fosfatidylinositol-3-kinasy MeSH
• inhibitory fosfoinositid-3-kinasy MeSH
• inhibitory proteinkinas MeSH
• protoonkogenní proteiny c-akt MeSH
• TOR serin-threoninkinasy MeSH

Increased activity of the Src tyrosine protein kinase that has been observed in a large number of human malignancies appears to be a promising target for drug therapy. In the present study, a critical role of the Src activity in the deregulation of mTOR signaling pathway in Rous sarcoma virus (RSV)-transformed hamster fibroblasts, H19 cells, was shown using these cells treated with the Src-specific inhibitor, SU6656, and clones of fibroblasts expressing either the active Src or the dominant-negative Src kinase-dead mutant. Disruption of the Src kinase activity results in substantial reduction of the phosphorylation and activity of the Akt/protein kinase B (PKB), phosphorylation of tuberin (TSC2), mammalian target of rapamycin (mTOR), S6K1, ribosomal protein S6, and eukaryotic initiation factor 4E-binding protein 4E-BP1. The ectopic, active Akt1 that was expressed in Src-deficient cells significantly enhanced phosphorylation of TSC2 in these cells, but it failed to activate the inhibited components of the mTOR pathway that are downstream of TSC2. The data indicate that the Src kinase activity is essential for the activity of mTOR-dependent signaling pathway and suggest that mTOR targets may be controlled by Src independently of Akt1/TSC2 cascade in cells expressing hyperactive Src protein. These observations might have an implication in drug resistance to mTOR inhibitor-based cancer therapy in certain cell types.

• MeSH
• Adenoviridae genetika   MeSH
• buněčné linie MeSH
• fosforylace MeSH
• indoly farmakologie   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• křečci praví MeSH
• proteinkinasy metabolismus   MeSH
• signální transdukce MeSH
• sulfonamidy farmakologie   MeSH
• transformované buněčné linie MeSH
• virus Rousova sarkomu genetika   MeSH
• zvířata MeSH
• Check Tag
• křečci praví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• indoly MeSH
• inhibitory proteinkinas MeSH
• proteinkinasy MeSH
• SU 6656 MeSH Prohlížeč
• sulfonamidy MeSH

BACKGROUND: PTEN is a tumour suppressor protein with phosphatase activity frequently altered in several types of human cancers. MATERIALS AND METHODS: The PTEN effect was studied on the cell cycle (by bromdeoxyuridine incorporation) and on the phosphatidylinositol-3-kinase/protein kinase B/Akt (PI3-K/PKB/Akt) pathway regulating proteins (by immunocytochemical, Western blot analysis and kinase assay) upon transfection of wild-type PTEN and its mutant H123Y in breast cancer cell lines. RESULTS: The expression of the important proteins in the MCF-7 and BT-549 cells was characterised and the cellular localisation of PTEN was analysed. Transfection of H123Y led to the down-regulation of p27(Kip1) and p21(Waf1/Cip1) protein levels and the up-regulation of phosphorylated PKB/Akt. An overexpression of PTEN decreased cyclin E/cdk2 activity and inhibited S-phase entry in MCF-7. In BT-549 these changes were not observed, but overexpression of PTEN led to a diminution of PKB/Akt phosphorylation. CONCLUSION: PTEN function is mediated through the inhibition of the cell cycle and PKB/Akt phosphorylation in breast cancer cells.

• MeSH
• buněčný cyklus fyziologie   MeSH
• cyklin D MeSH
• cyklin-dependentní kinasa 2 metabolismus   MeSH
• cykliny biosyntéza   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• fosfohydroláza PTEN biosyntéza   genetika   metabolismus   MeSH
• fosforylace MeSH
• inhibitor p21 cyklin-dependentní kinasy biosyntéza   MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory prsu enzymologie   genetika   metabolismus   patologie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• S fáze fyziologie   MeSH
• transfekce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CDK2 protein, human MeSH Prohlížeč
• CDKN1A protein, human MeSH Prohlížeč
• CDKN1B protein, human MeSH Prohlížeč
• cyklin D MeSH
• cyklin-dependentní kinasa 2 MeSH
• cykliny MeSH
• fosfatidylinositol-3-kinasy MeSH
• fosfohydroláza PTEN MeSH
• inhibitor p21 cyklin-dependentní kinasy MeSH
• inhibitor p27 cyklin-dependentní kinasy MeSH
• intracelulární signální peptidy a proteiny MeSH
• protoonkogenní proteiny c-akt MeSH
• PTEN protein, human MeSH Prohlížeč

The pro-metastatic protein anterior gradient-2 (AGR2) was previously demonstrated as a predictive factor of poor response to tamoxifen treatment. In this study we aimed to delineate the key signalling pathway that may contribute to regulation of AGR2 protein induction in order to identify novel targets to overcome tamoxifen resistance in tumour cells. Together, our data identify PDPK1-AKT as a pro-oncogenic signalling pathway that triggers AGR2 protein induction in response to tamoxifen and suggest that AKT inhibitors could be used as part of a therapeutic strategy to treat tamoxifen resistant, AGR2 over-expressing cancers.

• MeSH
• antitumorózní látky hormonální farmakologie   MeSH
• lidé MeSH
• mikro RNA MeSH
• molekulární sekvence - údaje MeSH
• mukoproteiny MeSH
• nádorové buněčné linie MeSH
• nádory prsu farmakoterapie   metabolismus   patologie   MeSH
• onkogenní proteiny MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy PDK MeSH
• proteiny genetika   metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• ribonukleosidy farmakologie   MeSH
• sekvence nukleotidů MeSH
• serin metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• tamoxifen farmakologie   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• AGR2 protein, human MeSH Prohlížeč
• antitumorózní látky hormonální MeSH
• mikro RNA MeSH
• mukoproteiny MeSH
• onkogenní proteiny MeSH
• PDPK1 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• proteinkinasy PDK MeSH
• proteiny MeSH
• protoonkogenní proteiny c-akt MeSH
• ribonukleosidy MeSH
• serin MeSH
• tamoxifen MeSH
• triciribine MeSH Prohlížeč

This study investigated whether kaempferol could inhibit ovarian cancer (OC) by activation of endoplasmic reticulum (ER) stress and autophagy, and tested its effect on the sensitivity of OC cells to cisplatin (cis-diamminedichloroplatinum, DPP). To study the effect of kaempferol on activation of ER stress and autophagy and find out whether its mechanism of action involves calcium (Ca2+), A2780 OC cells were cultured in DMEM/F12 for 24 h with or without kaempferol (40 μmol/l) in the presence or absence of autophagy or ER stress inhibitors or a calcium chelator. To study the effect of kaempferol on the sensitivity of OC cells to DPP and the potential involvement of modulation of protein kinase B (Akt) expression, A2780 OC were incubated with kaempferol and increasing concentrations of DPP (0-20 μmol/l) and then with kaempferol at its predetermined IC50 (6.8 μmol/l). Compared to control cells, kaempferol increased cell apoptosis (158 %) and decreased viability (53.17 %) and proliferation (49.17 %) of A2780 OC cells. Concomitantly, it increased the protein levels of GRP78, PERK, ATF6, IRE-1, LC3II, beclin 1, and caspase 4, thus suggesting activation of cytotoxic autophagy. This was mediated by increasing intracellular Ca+2 levels. In addition, kaempferol increased the sensitivity of A2780 cells to DPP (IC50 from 6.867 ± 0.99 to 3.73 ± 0.59 μmol/l) by decreasing the protein levels of p-Akt (0.31 ± 0.09 vs 0.12 ± 0.005). In conclusion, the findings of this study encourage the use of kaempferol alone or in combination with DPP to inhibit tumorigenesis of ovarian cells.

• MeSH
• apoptóza MeSH
• autofagie * MeSH
• chaperon endoplazmatického retikula BiP MeSH
• cisplatina farmakologie   MeSH
• kempferoly farmakologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory vaječníků patologie   MeSH
• protoonkogenní proteiny c-akt antagonisté a inhibitory   metabolismus   MeSH
• signální transdukce MeSH
• stres endoplazmatického retikula účinky léků   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• chaperon endoplazmatického retikula BiP MeSH
• cisplatina MeSH
• HSPA5 protein, human MeSH Prohlížeč
• kempferoly MeSH
• protoonkogenní proteiny c-akt MeSH

Macranthoside B (MB) is a triterpenoid saponin extracted from Lonicera macranthoides, a traditional Chinese medicine. In the current study, we investigated the anticancer potential of MB in various cancer cells and elucidated its underlying mechanisms. MB exposure inhibited cell proliferation, induced mitochondrial membrane potential (MMP) loss, increased sub-G1 accumulation, and resulted in cleavage of caspase-3 and PARP, which are reflective of apoptosis. In HeLa cells, MB induced down-regulation of SOD2 and GPx1, phosphorylation of Akt and PDK1, and thus promoted ROS-mediated apoptosis. This was further supported by the protection of sub-G1 accumulation, MMP loss, cleavage of caspase-3 and PARP in the presence of N-acetylcysteine (NAC). Additionally, MB induced cell death via down-regulation of ubiquitin-like with PHD and ringfinger domains 1 (UHRF1) and Bcl-xL. Taken together, this study provides a new insight into the apoptosis- inducing potential of MB, and its molecular mechanisms are associated with an increase in oxidative stress and inhibition of the PDK1/Akt pathway.

• MeSH
• adenokarcinom * MeSH
• apoptóza MeSH
• HeLa buňky MeSH
• kaspasa 3 metabolismus   MeSH
• lidé MeSH
• membránový potenciál mitochondrií MeSH
• nádorové buněčné linie MeSH
• PARP inhibitory farmakologie   MeSH
• proteiny vázající zesilovač transkripce CCAAT metabolismus   farmakologie   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• reaktivní formy kyslíku metabolismus   MeSH
• saponiny * farmakologie   MeSH
• ubikvitinligasy metabolismus   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kaspasa 3 MeSH
• macranthoside B MeSH Prohlížeč
• PARP inhibitory MeSH
• proteiny vázající zesilovač transkripce CCAAT MeSH
• protoonkogenní proteiny c-akt MeSH
• reaktivní formy kyslíku MeSH
• saponiny * MeSH
• ubikvitinligasy MeSH
• UHRF1 protein, human MeSH Prohlížeč