UNIPROT:P31749 - FACTA Search

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Query: UNIPROT:P31749 (AKT)
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Although increasing evidence supports a link between epidermal growth factor receptor (EGFR) signaling and resistance to apoptosis, the mechanism by which the EGFR signaling pathway inhibits apoptosis is not well understood. In this study, we found that epidermal growth factor (EGF) stimulation increased the level of expression of the inhibitor of apoptosis protein survivin in breast cancer cells but not in normal mammary epithelial cells. We further demonstrated that activation of survivin gene expression is mediated by oxygen-independent hypoxia-inducible factor (HIF)-1alpha up-regulation in EGF-treated cancer cells. EGFR signaling activated the phosphoinositide 3-kinase/AKT pathway, subsequently increasing the level of HIF-1alpha under normoxic conditions. HIF-1alpha then activated survivin gene transcription through direct binding to the survivin promoter. Furthermore, we found that overexpression of HIF-1alpha small interfering RNA blocks EGF-induced survivin gene up-regulation and increases apoptosis induced by the chemotherapy drug docetaxel. However, transfection of a plasmid expressing HIF-1alpha gene activates survivin gene expression and reduces the apoptotic response. Our results demonstrate a novel pathway for EGFR signaling-mediated apoptosis resistance in human cancer cells. Although the role of HIF-1alpha in regulating cell survival under hypoxic conditions has been studied extensively, our results show that normoxic breast cancer cells utilize cross-talk between EGFR signals and HIF-1alpha to up-regulate the anti-apoptotic survivin gene, providing a strong rationale for the targeting of HIF-1alpha as a therapeutic approach for both hypoxic and normoxic tumor cells. Understanding key molecular events in EGFR signaling-induced apoptosis resistance should provide new information for the development of novel therapeutic agents targeting EGFR, HIF-1alpha, and/or survivin.
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PMID:Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. 1684 54

EGFR is involved in the UV signal transduction pathway leading to skin cancer. UV radiation, mediated by EGFR, induces activation of PI3 kinase and AKT with a result of activation of a number of transcription factors. Transcription factor HIF-1alpha correlates with tumorigenicity and angiogenesis. Transcription factors DEC1 and DEC2 also play pivotal roles in multiple signaling pathways impacting various biological processes including development, cell differentiation, cell death, and oncogenesis. We investigated whether UV radiation and associated hypoxia induce expression of HIF-1alpha and its target genes such as VEGF and the signaling pathway mediating such responses. We found that UV radiation induced HIF-1alpha and VEGF protein expression in a dose- and time-dependent manner in cultured human keratinocytes. UV radiation also induced VEGF mRNA expression in a dose-dependent manner with maximum effect at 4 h post treatment, but did not affect HIF-1alpha mRNA expression. We also observed that UV radiation induced activation of EGFR in a time- and dose-dependent manner which was inhibited by EGFR inhibitor PD153035. In egfr (-/-) MEF cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in egfr (+/+) MEF cells, UV radiation strongly induced HIF-1alpha and VEGF expression. EGFR kinase inhibitor, PD153035, inhibited UV-induced HIF-1alpha and VEGF protein expression in a dose-dependent manner. Further, we found that PI3K inhibitors, LY294002 and Wortmannin, inhibited HIF-1alpha and VEGF expression induced by UV radiation. In DEC1 (-/-) HaCat cells, UV radiation did not induce HIF-1alpha and VEGF expression, in contrast, in DEC1 (+/+) HaCat cells, UV radiation strongly enhanced HIF-1alpha and VEGF protein expression. We conclude that UV radiation induces HIF-1alpha and VEGF expression via the EGFR/PI3K/DEC1 signaling pathway.
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PMID:UVB radiation induces expression of HIF-1alpha and VEGF through the EGFR/PI3K/DEC1 pathway. 1696 27

The epidermal growth factor (EGF) and EGF receptor (EGFR) family are often overexpressed in various human cancers including ovarian cancer. While it is generally believed that reactive oxygen species (ROS) are involved in the intracellular signaling events, the role of ROS in EGF-induced angiogenesis and carcinogenesis remains to be elucidated. The present study investigated the role of ROS in the regulation of AKT, p70S6K1, vascular endothelial growth factor (VEGF), and hypoxia-inducible factor 1 (HIF-1) in ovarian cancer cells. In this study, OVCAR-3 cells were treated with EGF and catalase, an H2O2 scavenger. EGF treatment increases H2O2 production, leading to activation of the AKT/p70S6K1 pathway, resulting in increased VEGF expression at the transcriptional level. The inhibition of H(2)O(2) production by catalase abolished EGF-induced AKT and p70S6K1 activation, and VEGF expression through HIF-1alpha expression. Forced expression of p70S6K1 and HIF-1alpha reversed catalase- and rapamycin-inhibited VEGF transcriptional activation. We also showed that rapamycin, p70S6K1 inhibitor and catalase overexpression inhibited tumor angiogenesis. This study demonstrates a novel mechanism of EGF-induced VEGF and HIF-1alpha expression through production of H2O2 and activation of AKT and p70S6K1 in human ovarian cancer cells. This study also indicates that p70S6K1 and H2O2 are important in tumor angiogenesis. The results of the study could have an important implication in ovarian cancer therapy.
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PMID:Reactive oxygen species regulate epidermal growth factor-induced vascular endothelial growth factor and hypoxia-inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. 1704 20

The last decade has seen the molecular chaperone heat shock protein 90 (HSP90) emerge as an exciting target for cancer therapy. This is because HSP90 is involved in maintaining the conformation, stability, activity and cellular localisation of several key oncogenic client proteins. These include, amongst others, ERBB2, C-RAF, CDK4, AKT/PKB, steroid hormone receptors, mutant p53, HIF-1alpha , survivin and telomerase hTERT. Therefore, modulation of this single drug target offers the prospect of simultaneously inhibiting all the multiple signalling pathways and biological processes that have been implicated in the development of the malignant phenotype. The chaperone function of HSP90 requires the formation of a multichaperone complex, which is dependent on the hydrolysis of ATP and ADP/ATP exchange. Most current inhibitors of HSP90 act as nucleotide mimetics, which block the intrinsic ATPase activity of this molecular chaperone. The first-in-class inhibitor to enter and complete phase I clinical trials was the geldanamycin analogue, 17-allylamino-17-demethoxygeldanamycin. The results of these trials have demonstrated that HSP90 is a valid drug target. Evidence of clinical activity has been seen in patients with melanoma, breast and prostate cancer. This article provides a personal perspective of the present efforts to increase our understanding of the molecular and cellular consequences of HSP90 inhibition, with examples from work in our own laboratory. We also review the discovery and development of novel small-molecule inhibitors and discuss alternative approaches to inhibit HSP90 activity, both of which offer exciting prospects for the future.
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PMID:Targeting of multiple signalling pathways by heat shock protein 90 molecular chaperone inhibitors. 1725 53

Biomarkers to predict or monitor therapy response are becoming essential components of drug developer's armamentaria. Molecular and functional imaging has particular promise as a biomarker for anticancer therapies because it is non-invasive, can be used longitudinally and provides information on the whole patient or tumor. Despite this promise, molecular or functional imaging endpoints are not routinely incorporated into clinical trial design. As the costs of clinical trials and drug development become prohibitively more expensive, the need for improved biomarkers has become imperative and thus, the relatively high cost of imaging is justified. Imaging endpoints, such as Diffusion-Weighted MRI, DCE-MRI and FDG-PET have the potential to make drug development more efficient at all phases, from discovery screening with in vivo pharmacodynamics in animal models through the phase III enrichment of the patient population for potential responders. This review focuses on the progress of imaging responses to new classes of anti-cancer therapies targeted against PI3 kinase/AKT, HIF-1alpha and VEGF. The ultimate promise of molecular and functional imaging is to theragnostically predict response prior to commencement of targeted therapy.
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PMID:Promise and progress for functional and molecular imaging of response to targeted therapies. 1738 18

PI3K pathway exerts its function through its downstream molecule AKT in regulating various cell functions including cell proliferation, cell transformation, cell apoptosis, tumor growth and angiogenesis. PTEN is an inhibitor of PI3K, and its loss or mutation is common in human prostate cancer. But the direct role and mechanism of PI3K/PTEN signaling in regulating angiogenesis and tumor growth in vivo remain to be elucidated. In this study, by using chicken chorioallantoic membrane (CAM) and in nude mice models, we demonstrated that inhibition of PI3K activity by LY294002 decreased PC-3 cells-induced angiogenesis. Reconstitution of PTEN, the molecular inhibitor of PI3K in PC-3 cells inhibited angiogenesis and tumor growth. Immunohistochemical staining indicated that PTEN expression suppressed HIF-1alpha, VEGF and PCNA expression in the tumor xenographs. Similarly, expression of AKT dominant negative mutant also inhibited angiogenesis and tumor growth, and decreased the expression of HIF-1alpha and VEGF in the tumor xenographs. These results suggest that inhibition of PI3K signaling pathway by PTEN inhibits tumor angiogenesis and tumor growth. In addition, we found that AKT is the downstream target of PI3K in controlling angiogenesis and tumor growth, and PTEN could inhibit angiogenesis by regulating the expression of HIF-1 and VEGF expression through AKT activation in PC-3 cells.
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PMID:PI3K/PTEN/AKT signaling regulates prostate tumor angiogenesis. 1782 33

The oxygen sensitive alpha-subunit of the hypoxia-inducible factor-1 (HIF-1) is a major trigger of the cellular response to hypoxia. Although the posttranslational regulation of HIF-1alpha by hypoxia is well known, its transcriptional regulation by hypoxia is still under debate. We, therefore, investigated the regulation of HIF-1alpha mRNA in response to hypoxia in pulmonary artery smooth muscle cells. Hypoxia rapidly enhanced HIF-1alpha mRNA levels and HIF-1alpha promoter activity. Furthermore, inhibition of the phosphatidylinositol 3-kinase (PI3K)/AKT but not extracellular signal-regulated kinase 1/2 pathway blocked the hypoxia-dependent induction of HIF-1alpha mRNA and HIF-1alpha promoter activity, suggesting involvement of a PI3K/AKT-regulated transcription factor. Interestingly, hypoxia also induced nuclear factor-kappaB (NFkappaB) nuclear translocation and activity. In line, expression of the NFkappaB subunits p50 and p65 enhanced HIF-1alpha mRNA levels, whereas blocking of NFkappaB by an inhibitor of nuclear factor-kappaB attenuated HIF-1alpha mRNA induction by hypoxia. Reporter gene assays revealed the presence of an NFkappaB site within the HIF-1alpha promoter, and mutation of this site abolished induction by hypoxia. In line, gel shift analysis and chromatin immunoprecipitation confirmed binding of p50 and p65 NFkappaB subunits to the HIF-1alpha promoter under hypoxia. Together, these findings provide a novel mechanism in which hypoxia induces HIF-1alpha mRNA expression via the PI3K/AKT pathway and activation of NFkappaB.
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PMID:Hypoxia up-regulates hypoxia-inducible factor-1alpha transcription by involving phosphatidylinositol 3-kinase and nuclear factor kappaB in pulmonary artery smooth muscle cells. 1789 80

Underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in cancer cells are diverse and cell type specific. Although both HIF-1alpha and AKT (protein kinase B) have been implicated in gastric tumor promotion and angiogenesis, it remains unclear whether HIF-1 mediates the role of AKT in terms of promoting vascular endothelial growth factor (VEGF) expression. The present study was performed to investigate the correlation between HIF-1alpha activation and AKT activation in gastric cancer using human gastric cancer specimens, in vitro cell experiments and in vivo animal experiments. Immunohistochemistry performed on tissue array slides containing 268 surgical specimens of gastric carcinomas showed immunoreactivity for HIF-1alpha in 29% of samples. Moreover, HIF-1alpha was positively associated with phosphorylated AKT (pAKT) (P = 0.002) or VEGF (P = 0.002), and the immunoreactivities of pAKT and VEGF were positively correlated (P < 0.001). Western blot analysis and reverse transcription-polymerase chain reaction in cell experiments revealed that the over-expression of constitutively active AKT (CA-AKT) promotes the expressions of HIF-1alpha protein and VEGF messenger ribonucleic acid in Seoul national university (SNU)-216 and SNU-668 gastric cancer cells under normoxic conditions, whereas kinase-dead mutant of AKT down-regulated these expressions under the same conditions. Xenografts in nude mice derived from stable gastric cancer cells over-expressing CA-AKT showed higher tumor incidence, larger tumor volumes, higher microvessel density and stronger HIF-1alpha immunoreactivity than those derived from vector control cells. Thus, we propose that the hypoxia-independent promotion of the AKT-HIF-1alpha-VEGF pathway contributes, at least in part, to gastric cancer tumorigenesis and angiogenesis.
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PMID:A hypoxia-independent up-regulation of hypoxia-inducible factor-1 by AKT contributes to angiogenesis in human gastric cancer. 1798 17

Photodynamic therapy (PDT) using 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PPIX) is clinically established approach for a number of defined applications. However, in order to optimize the therapeutic benefits of PDT, the specific mode of cell destruction should be better defined. Apoptosis is favored over necrosis for clinical practice as the latter causes more side-effects. In the present study, we analyse PDT-induced cell death and its correlation to various PDT parameters (different doses applied, time after PDT treatment) in vitro using reverse phase protein arrays. Human urothelial cell lines with varying degrees of differentiation (UROtsa, RT4, RT112, J82) were subjected to in vitro-PDT using increasing doses of irradiation. In addition, positive controls for apoptosis, necrosis and un-/specific cellular damage were included. Cells were harvested over a specified time course, lysed and arrayed onto nitrocellulose-covered glass slides. The arrays were analyzed for expression of apoptosis-related proteins by immunohistochemistry. Analysis of caspase-3 and -9 expression, the activation of HIF-1alpha, Bcl2, Cox2 and the phosphorylation of AKT reveals signal activation due to a PDT-stimulus in correlation with the positive controls. Data were analyzed by unsupervised hierarchical clustering and depicted as a heat map revealing cell-specific patterns of pathway stimulation. Higher differentiated phenotypes showed a more distinct signal response in general and a higher apoptotic response in detail. Lower differentiated cell lines lost pathway regulation capabilities according to their state of dedifferentiation. Reverse phase protein arrays are a promising technique for signal pathway profiling: they exceed the range of traditional western blots by sensitivity, high-throughput capability, minimal sample consumption and easy quantification of results obtained.
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PMID:Analyzing effects of photodynamic therapy with 5-aminolevulinic acid (ALA) induced protoporphyrin IX (PPIX) in urothelial cells using reverse phase protein arrays. 1804 85

Inactivating mutations in NF1 underlie the prevalent familial cancer syndrome neurofibromatosis type 1 [1]. The NF1-encoded protein is a Ras GTPase-activating protein (RasGAP) [2]. Accordingly, Ras is aberrantly activated in NF1-deficient tumors; however, it is unknown which effector pathways critically function in tumor development. Here we provide in vivo evidence that TORC1/mTOR activity is essential for tumorigenesis. Specifically, we show that the mTOR inhibitor rapamycin potently suppresses the growth of aggressive NF1-associated malignancies in a genetically engineered murine model. However, in these tumors rapamycin does not function via mechanisms generally assumed to mediate tumor suppression, including inhibition of HIF-1alpha and indirect suppression of AKT, but does suppress the mTOR target Cyclin D1 [3]. These results demonstrate that mTOR inhibitors may be an effective targeted therapy for this commonly untreatable malignancy. Moreover, they indicate that mTOR inhibitors do not suppress all tumor types via the same mechanism, suggesting that current biomarkers that rely on HIF-1alpha suppression may not be informative for all cancers. Finally, our results reveal important differences between the effects of mTOR inhibition on the microvasculature in genetically engineered versus xenograft models and indicate that the former may be required for effective preclinical screening with this class of inhibitors.
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PMID:TORC1 is essential for NF1-associated malignancies. 1816 2

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