Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P31749 (AKT)
 22,954 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

RNA-dependent protein kinase is an interferon-induced, double-stranded (ds), RNA-activated serine/threonine protein kinase involved in the eukaryotic response to viral infection. While PKR also functions in cellular differentiation, growth control and apoptosis, its role in human cancer remains poorly understood. To explore a role for PKR in human cancer, we evaluated PKR expression and function in a series of cancer cell lines from different tumor types. We observed that PKR protein expression is high in various cancer cells and low in normal cells. Knockdown of PKR protein expression by PKR siRNA induced cell death, indicating a PKR-dependent survival pathway under normal growth conditions. Inhibition of PKR signaling using a dominant negative adenoviral PKR mutant (Ad-Delta6PKR) also induced cancer cell apoptosis via a mechanism that blocks activation of AKT-mediated survival while simultaneously inducing ER stress. ER stress-mediated apoptosis was evidenced by unregulated expression of phosphorylated JNK (p-JNK), phosphorylated cJun (p-cJun), and caspase-4 and was significantly reduced in cancer cells treated with JNK and caspase-4 inhibitors. We further demonstrated that inhibition of PKR signaling via either siRNA or Ad-Delta6PKR sensitizes cancer cells to etoposide or cisplatin-mediated cell death. Our results suggest a rationale to develop therapeutic strategies that target PKR signaling in human cancer cells.
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PMID:Inhibition of RNA-dependent protein kinase (PKR) leads to cancer cell death and increases chemosensitivity. 1910 40

The aim of this study was to investigate the involvement of the serine/threonine protein kinase AKT (also called protein kinase B) in the control of meiosis of porcine denuded oocytes (DOs) matured in vitro. Western blot analysis revealed that the two principal AKT phosphorylation sites, Ser473 and Thr308, are phosphorylated at different stages of meiosis. In freshly isolated germinal vesicle (GV)-stage DOs, Ser473 was already phosphorylated. After the onset of oocyte maturation, the intensity of the Ser473 phosphorylation increased, however, which declined sharply when DOs underwent GV breakdown (GVBD) and remained at low levels in metaphase I- and II-stage (MI- and MII-stage). In contrast, phosphorylation of Thr308 was increased by the time of GVBD and reached maximum at MI-stage. A peak of AKT activity was noticed around GVBD and activity of AKT declined at MI-stage. To assess the role of AKT during meiosis, porcine DOs were cultured in 50 microM SH-6, a specific inhibitor of AKT. In SH-6-treated DOs, GVBD was not inhibited; on the contrary, a significant acceleration of meiosis resumption was observed. The dynamics of the Ser473 phosphorylation was not affected; however, phosphorylation of Thr308 was reduced, AKT activity was diminished at the time of GVBD, and meiotic progression was arrested in early MI-stage. Moreover, the activity of the cyclin-dependent kinase 1 (CDK1) and MAP kinase declined when SH-6-treated DOs underwent GVBD, indicating that AKT activity is involved in the regulation of CDK1 and MAP kinase. These results suggest that activity of AKT is not essential for induction of GVBD in porcine oocytes but plays a substantial role during progression of meiosis to MI/MII-stage.
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PMID:AKT (protein kinase B) is implicated in meiotic maturation of porcine oocytes. 1963 30

The herpes simplex virus type 1 (HSV-1) latency-associated transcript (LAT) is expressed abundantly in latently infected sensory neurons. LAT-deletion-mutant virus strains have reduced-reactivation phenotypes in small animal models of infection, demonstrating that LAT plays an important role in the latency-reactivation cycle of HSV-1. Previous studies demonstrated that the anti-apoptosis functions of LAT are important for regulating the latency-reactivation cycle because three different anti-apoptosis genes can substitute for LAT. Although LAT inhibits caspase 3 activation, the signalling pathway by which LAT inhibits caspase 3 activation was not identified. In this study, we analysed mouse neuroblastoma cells (C1300) that express LAT stably (DC-LAT6 cells) following serum starvation. As expected, DC-LAT6 cells were resistant to apoptosis following serum withdrawal. Levels of total and phosphorylated AKT (protein kinase B), a serine/threonine protein kinase that promotes cell survival, were higher in DC-LAT6 cells after serum withdrawal than in C1300 cells or a cell line stably transfected with a LAT promoter mutant (DC-DeltaLAT311). A specific AKT inhibitor reduced the anti-apoptosis functions of LAT and phosphorylated AKT levels. After serum withdrawal, more DC-LAT6 cells sprouted neurites and exhibited a differentiated morphology. NeuN (neuronal nuclei), a neuron-specific nuclear protein, was expressed abundantly in DC-LAT6 cells, but not C1300 cells, after serum withdrawal, further supporting the concept that LAT enhanced neuronal-like morphology. Collectively, these studies suggested that LAT, directly or indirectly, maintained total and phosphorylated AKT levels, which correlated with increased cell survival and mature neuronal-like morphology.
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PMID:Herpes simplex virus type 1 latency-associated transcript inhibits apoptosis and promotes neurite sprouting in neuroblastoma cells following serum starvation by maintaining protein kinase B (AKT) levels. 1995 63

Protein kinase B (PKB/Akt) is a serine/threonine protein kinase that created serious interest when it was revealed as a mediator of the PI3K pathway. It comprises three isoforms that play both unique and redundant roles. Upon binding to phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) generated by PI3K, PKB is phosphorylated by PDK1 at T308. To achieve full kinase activity, PKB needs to be phosphorylated at a second key residue, S473, by members of the PI3K-related kinase family mTORC2 or DNA-PK, depending on the stimulus and the context. Besides, a number of phosphatases and interacting partners have been shown to further modulate its subcellular localization, phosphorylation, and kinase activity. This review aims at illustrating the remarkable complexity in the regulation of PKB signaling downstream of PI3K. Such regulation could be attributed to the specific roles of the PKB isoforms, their expression pattern, subcellular localization, targets, phosphorylation by upstream kinases in a stimulus- and context-dependent manner and by phosphatases, and interaction with binding partners. This allows this key kinase to fulfill physiological functions in numerous processes, including embryonic development, thymocyte development, adipocyte differentiation, glucose homeostasis, and to avoid pathological loss of control such as tumor formation.
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PMID:Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway. 2051 22

It has been recently shown that a short sublethal brain ischemia subsequent to a prolonged harmful ischemic episode may confer ischemic neuroprotection, a phenomenon termed ischemic postconditioning. Na(+)/Ca(2+) exchanger (NCX) isoforms, NCX1, NCX2, and NCX3, are plasma membrane ionic transporters widely distributed in the brain and involved in the control of Na(+) and Ca(2+) homeostasis and in the progression of stroke damage. The objective of this study was to evaluate the role of these three proteins in the postconditioning-induced neuroprotection. The NCX protein and mRNA expression was evaluated at different time points in the ischemic temporoparietal cortex of rats subjected to tMCAO alone or to tMCAO plus ischemic postconditioning. The results of this study showed that NCX3 protein and ncx3 mRNA were upregulated in those brain regions protected by postconditioning treatment. These changes in NCX3 expression were mediated by the phosphorylated form of the ubiquitously expressed serine/threonine protein kinase p-AKT, as the p-AKT inhibition prevented NCX3 upregulation. The relevant role of NCX3 during postconditioning was further confirmed by results showing that NCX3 silencing, induced by intracerebroventricular infusion of small interfering RNA (siRNA), partially reverted the postconditioning-induced neuroprotection. The results of this study support the idea that the enhancement of NCX3 expression and activity might represent a reasonable strategy to reduce the infarct extension after stroke.
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PMID:The NCX3 isoform of the Na+/Ca2+ exchanger contributes to neuroprotection elicited by ischemic postconditioning. 2062 98

Physical exercise is a widely accepted behavioral strategy to enhance overall health, including mental function. However, there is controversial evidence showing brain mitochondrial dysfunction, oxidative damage and decreased neurotrophin levels after high-intensity exercise, which presumably worsens cognitive performance. Here we investigated learning and memory performance dependent on different brain regions, glutathione antioxidant system, and extracellular signal-regulated protein kinase 1/2 (ERK1/2), serine/threonine protein kinase (AKT), cAMP response element binding (CREB) and dopamine- and cyclic AMP-regulated phosphoprotein (DARPP)-32 signaling in adult Swiss mice submitted to 9 weeks of high-intensity exercise. The exercise did not alter the animals' performance in the reference and working memory versions of the water maze task. On the other hand, we observed a significant impairment in the procedural memory (an implicit memory that depends on basal ganglia) accompanied by a reduced antioxidant capacity and ERK1/2 and CREB signaling in this region. In addition, we found increased striatal DARPP-32-Thr-75 phosphorylation in trained mice. These findings indicate an increased vulnerability of the striatum to high-intensity exercise associated with the disruption of implicit memory in mice and accompanied by alteration of signaling proteins involved in the plasticity of this brain structure.
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PMID:High-intensity physical exercise disrupts implicit memory in mice: involvement of the striatal glutathione antioxidant system and intracellular signaling. 2088 97

Urokinase plasminogen activator receptor (uPAR) is a multidomain protein that plays important roles in the growth, invasion, and metastasis of a number of cancers. In the present study, we examined the effects of administration of a monoclonal anti-uPAR antibody (ATN-658) on prostate cancer progression in vitro and in vivo. We examined the effect of treatment of ATN-658 on human prostate cancer cell invasion, migration, proliferation, and regulation of intracellular signaling pathways. For in vivo studies, PC-3 cells (1 x 10(6)) were inoculated into the right flank of male Balb C nu/nu mice through subcutaneous or through intratibial route (2 x 10(5)) of male Fox Chase severe combined immunodeficient mice to monitor the effect on tumor growth and skeletal metastasis. Treatment with ATN-658 resulted in a significant dose-dependent decrease in PC-3 cell invasion and migration without affecting cell doubling time. Western blot analysis showed that ATN-658 treatment decreased the phosphorylation of serine/threonine protein kinase B (AKT), mitogen-activated protein kinase (MAPK), and focal adhesion kinase (FAK) without affecting AKT, MAPK, and FAK total protein expression. In in vivo studies, ATN-658 caused a significant decrease in tumor volume and a marked reduction in skeletal lesions as determined by Faxitron x-ray and micro-computed tomography. Immunohistochemical analysis of subcutaneous and tibial tumors showed a marked decrease in the levels of expression of pAKT, pMAPK, and pFAK, consistent with the in vitro observations. Results from these studies provide compelling evidence for the continued development of ATN-658 as a potential therapeutic agent for the treatment of prostate and other cancers expressing uPAR.
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PMID:An anti-urokinase plasminogen activator receptor antibody (ATN-658) blocks prostate cancer invasion, migration, growth, and experimental skeletal metastasis in vitro and in vivo. 2092 16

Forkhead box O (FoxO) transcription factors are downstream targets of the serine/threonine protein kinase B (PKB)/Akt. The Akt kinase regulates processes of cellular proliferation and survival. Phosphorylation of FoxOs by Akt inhibits transcriptional functions of FoxOs and contributes to cell survival, growth and proliferation. Emerging evidence suggests involvement of FoxOs in diverse intracellular signaling pathways with critical roles in a number of physiological as well as pathological conditions including cancer. The FoxO signaling is regulated by their interactions with other intracellular proteins as well as their post-translational modifications such as phosphorylation. FoxOs promote cell growth inhibitory and/or apoptosis signaling by either inducing expression of multiple pro-apoptotic members of the Bcl2-family of mitochondria-targeting proteins, stimulating expression of death receptor ligands such as Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), or enhancing levels of various cyclin-dependent kinase inhibitors (CDKIs). Coupled with their ability to cross-talk with p53, FoxOs represent an important class of tumor suppressors in a variety of cancers. This review summarizes our current understanding of mechanisms by which Akt and FoxOs regulate cell growth and survival that in turn offers opportunities for development of novel strategies to combat cancer. This article is part of a Special Issue entitled: P13K-AKT-FOxO axis in cancer and aging.
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PMID:Akt, FoxO and regulation of apoptosis. 2144 11

Hepatocellular carcinoma (HCC) is one of the most frequent malignant neoplasms worldwide and is the second leading cause of cancer death in China. We have previously demonstrated that LAPTM4B-35, encoded by lysosomal protein transmembrane 4 beta gene, is overexpressed in over 80% of HCCs and is a novel-independent prognostic factor for metastasis, recurrence, and postoperative survival in HCC. In this study, we investigated the role of LAPTM4B-35 in malignant transformation and tumorigenesis using L02 cells, a cell line originated from human normal liver cells. Our data show that replication-deficient adenovirus vector-mediated upregulation of LAPTM4B-35 promotes anchorage-independent proliferation and resistance to adriamycin-induced apoptosis. Study of the underlying mechanisms demonstrated alterations of molecular events involved in these processes, which included the activation of phosphoinositide 3-kinases (PI3K)/serine/threonine protein kinase B (PKB/AKT)/bcl-xL/bcl-2-associated death promoter homolog (Bad) signaling pathway, inhibition of caspase-3 activation, upregulation of Bcl-2, and downregulation of Bax. In addition, upregulation of LAPTM4B-35 in L02 cells resulted in tumorigenesis in 100% (6/6) of inoculated nude mice and accelerated the death of mice with xenografts in vivo. In conclusion, LAPTM4B-35 promotes malignant transformation and tumorigenesis in human liver L02 cell line through promotion of deregulated proliferation and inhibition of apoptosis. These findings suggest that overexpression of LAPTM4B-35 may play a critical role in hepatocarcinogenesis and therefore, may be a therapeutic target for HCC.
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PMID:Upregulation of LAPTM4B-35 promotes malignant transformation and tumorigenesis in L02 human liver cell line. 2161 8

Protein kinase B (PKB, also called Akt) is known as a serine/threonine protein kinase. Some studies indicate that the Akt signalling pathway strongly promotes G2/M transition in mammalian cell cycle progression, but the mechanism remains to be clarified, especially in the fertilized mouse egg. Here, we report that the expression of Akt at both the protein and mRNA level was highest in G2 phase, accompanied by a peak of Akt activity. In addition, the subcellular localization of p21(Cip1/WAF1) has been proposed to be critical in the cell cycle. Hence, we detected the expression and localization of p21(Cip1/WAF1) after injecting fertilized mouse eggs with Akt mRNA. In one-cell stage fertilized embryos microinjected with mRNA coding for a constitutively active myristoylated Akt (myr-Akt), p21(Cip1/WAF1) was retained in the cytoplasm. Microinjection of mRNA of kinase-deficient Akt(Akt-KD) resulted in nuclear localization of p21(Cip1/WAF1) . Meanwhile, microinjection of different types of Akt mRNA affected the phosphorylation status of p21(Cip1/WAF1) . However, there was no obvious difference in the protein expression of p21(Cip1/WAF1) . Therefore, Akt controls the cell cycle by changing the subcellular localization of p21(Cip1/WAF1) , most likely by affecting the phosphorylation status of p21(Cip1/WAF1) .
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PMID:Protein kinase B/Akt may regulate G2/M transition in the fertilized mouse egg by changing the localization of p21(Cip1/WAF1). 2167 Dec 44


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