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)

The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration. Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma). The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm. The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon, endometrium, and breast have ties to these genes, highlighting the potential role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor, has potent antitumoral activities in preclinical models of TSC and is currently undergoing phase I/II clinical studies.
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PMID:The tuberous sclerosis complex genes in tumor development. 1556 17

The classic work of Hickson demonstrated that training for both strength and endurance at the same time results in less adaptation compared with training for either one alone: this has been described as the concurrent training effect. Generally, resistance exercise results in an increase in muscle mass, and endurance exercise results in an increase in muscle capillary density, mitochondrial protein, fatty acid-oxidation enzymes, and more metabolically efficient forms of contractile and regulatory proteins. In the 25 yr since Hickson's initial description, there have been a number of important advances in the understanding of the molecular regulation of muscle's adaptation to exercise that may enable explanation of this phenomenon at the molecular level. As will be described in depth in the following four papers, two serine/threonine protein kinases in particular play a particularly important role in this process. Protein kinase B/Akt can both activate protein synthesis and decrease protein breakdown, thus leading to hypertrophy, and AMP-activated protein kinase can increase mitochondrial protein, glucose transport, and a number of other factors that result in an endurance phenotype. Not only are PKB and AMPK central to the generation of the resistance and endurance phenotypes, they also block each other's downstream signaling. The consequence of these interactions is a direct molecular blockade hindering the development of the concurrent training phenotype. A better understanding of the activation of these molecular pathways after exercise and how they interact will allow development of better training programs to maximize both strength and endurance.
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PMID:Training for endurance and strength: lessons from cell signaling. 1709 27

The insulin-like growth factor 1 (IGF-1)-AKT-mTOR pathways sense the availability of nutrients and mitogens and respond by signaling for cell growth and division. The p53 pathway senses a variety of stress signals which will reduce the fidelity of cell growth and division, and responds by initiating cell cycle arrest, senescence, or apoptosis. This study explores four p53-regulated gene products, the beta1 and beta2 subunits of the AMPK, which are shown for the first time to be regulated by the p53 protein, TSC2, PTEN, and IGF-BP3, each of which negatively regulates the IGF-1-AKT-mTOR pathways after stress. These gene products are shown to be expressed under p53 control in a cell type and tissue-specific fashion with the TSC2 and PTEN proteins being coordinately regulated in those tissues that use insulin-dependent energy metabolism (skeletal muscle, heart, white fat, liver, and kidney). In addition, these genes are regulated by p53 in a stress signal-specific fashion. The mTOR pathway also communicates with the p53 pathway. After glucose starvation of mouse embryo fibroblasts, AMPK phosphorylates the p53 protein but does not activate any of the p53 responses. Upon glucose starvation of E1A-transformed mouse embryo fibroblasts, a p53-mediated apoptosis ensues. Thus, there is a great deal of communication between the p53 pathway and the IGF-1-AKT and mTOR pathways.
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PMID:The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. 1740 11

It is well known that exercise can have beneficial effects on insulin resistance by activation of glucose transporter. Following up our previous report that caveolin-1 plays an important role in glucose uptake in L6 skeletal muscle cells, we examined whether exercise alters the expression of caveolin-1, and whether exercise-caused changes are muscle fiber and exercise type specific. Fifty week-old Sprague Dawley (SD) rats were trained to climb a ladder and treadmill for 8 weeks and their soleus muscles (SOL) and extensor digitorum longus muscles (EDL) were removed after the last bout of exercise and compared with those from non-exercised animals. We found that the expression of insulin related proteins and caveolins did not change in SOL muscles after exercise. However, in EDL muscles, the expression of insulin receptor beta (IR beta) and glucose transporter-4 (GLUT-4) as well as phosphorylation of AKT and AMPK increased with resistance exercise but not with aerobic exercise. Also, caveolin-1 and caveolin-3 increased along with insulin related proteins only in EDL muscles by resistance exercise. These results suggest that upregulation of caveolin-1 in the skeletal muscle is fiber specific and exercise type specific, implicating the requirement of the specific mode of exercise to improve insulin sensitivity.
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PMID:Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle. 1760 94

Ultraviolet radiation (UV) induces apoptosis and functional maturation in skin dendritic cells (DCs). However, the molecular mechanisms through which UV activates DCs have not been thoroughly investigated. In this study, we examined the mechanisms of activation and apoptosis of DCs after UV irradiation by focusing on epidermal growth factor receptor (EGFR). Our previous studies have demonstrated that in addition to cognate ligands, EGFR is also activated by UVB irradiation in cultured human skin keratinocytes in vitro and in human skin in vivo. We found for the first time in this study that UV also induces EGFR activation in cultured mouse skin DCs (XS 106 cell line) as well as mouse monocyte-derived dendritic cells (MoDCs). Pharmacological inhibition of EGFR tyrosine kinase significantly inhibits UV-induced ERK, p38, and JNK MAP kinases, and their effectors, transcription factors c-Fos and c-Jun. Inhibition of EGFR also suppresses UV-induced activation of PI3K/AKT/mTOR/S6K and NF-kappaB signal transduction pathways. Our data demonstrated that UV induces LKB1/AMPK pathway, also dependent on EGFR trans-activation. We further observed that MAPK, LKB1/AMPK, PI3K/AKT/mTOR/S6K as well as NF-kappaB activation are impaired in EGFR-/- cells compared to wide type MEF cells after UV radiation. Taken together, we conclude that UV induces multiple signaling pathways mediated by EGFR trans-activation leading to possible maturation, apoptosis and survival, and EGFR activation protects against UV-induced apoptosis in cultured mouse dendritic cells.
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PMID:EGFR activation confers protections against UV-induced apoptosis in cultured mouse skin dendritic cells. 1864 33

The isolated perfused heart is an important model in cardiovascular research. We hypothesized that the perfusion procedure per se will phosphorylate some protein kinases important in pre- and postconditioning. Isolated hearts were Langendorff-perfused for 20 min with or without an intraventricular balloon (rats and mice), or in the working heart mode (mice) and compared to non-perfused controls with respect to protein phosphorylation. Rat hearts were also perfused for 20 and 50 min in the Langendorff mode to investigate the effect of perfusion time on phosphorylation. Western blot analysis showed that perfusion per se induced a massive phosphorylation of ERK 1/2, P38-MAPK, JNK, AMPK, but decreased phosphorylation of AKT in the isolated rat and mouse heart. However, during ongoing perfusion the phosphorylation of these kinases was reduced. Langendorff-perfusion without the intraventricular balloon caused less phosphorylation of ERK 1/2, P38-MAPK and JNK, but had no effect on AMPK. In working hearts phosphorylation of kinases was similar to that of Langendorff-perfused hearts without the balloon. Our findings indicate that excising, handling and perfusion induce a time dependent phosphorylation of stress kinases. The presence of the intraventricular balloon caused the strongest phosphorylation, thus Langendorff-perfused hearts might be partly protected by the perfusion procedure if stress kinases are protective in pre- and postconditioning. This might explain conflicting results obtained with different models of both pre- and postconditioning, and the isolated heart might in some situations be suboptimal for such studies.
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PMID:Inadvertent phosphorylation of survival kinases in isolated perfused hearts: a word of caution. 1919 17

Epidemiological and experimental evidence has supported the notion that solar ultraviolet (UV) radiation is the leading cause of skin cell damage and skin cancer. Non-melanoma skin cancer, one of the malignancies with the most rapidly increasing incidence, is suggested to be directly related to the total exposure to solar UV light. Over the past few years, the mechanisms of cellular responses to UV radiation have received unprecedented attention. Understanding how skin cells respond to UV radiation will undoubtedly help decipher what goes wrong in a variety of clinical skin disorders including skin cancer and will facilitate the development of novel therapeutic strategies. In the past decade, studies have established that UV radiation induces multifarious signal transduction pathways, some of which lead to apoptotic cell death, while others protect against this process. In this review, we summarize some of the most recent progresses regarding the involvement of multiple signal pathways in UV radiation-induced apoptosis in skin cells, especially in keratinocytes. These pathways include pro-apoptosis components such as MAPK, AMPK, and p53 as well as pro-survival components, namely, AKT and mTORC complexes.
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PMID:Parameters of protection against ultraviolet radiation-induced skin cell damage. 1936 Jul 45

Low serum levels of adiponectin are a high risk factor for various types of cancer. Although adiponectin inhibits proliferation and metastasis of breast cancer cells, the underlying molecular mechanisms remain obscure. In this study, we show that adiponectin-activated AMPK reduces the invasiveness of MDA-MB-231 cells by stimulating dephosphorylation of AKT by increasing protein phosphatase 2A (PP2A) activity. Among the various regulatory B56 subunits, B56gamma was directly phosphorylated by AMPK at Ser(298) and Ser(336), leading to an increase of PP2A activity through dephosphorylation of PP2Ac at Tyr(307). We also show that both the blood levels of adiponectin and the tissue levels of PP2A activity were decreased in breast cancer patients and that the direct administration of adiponectin into tumor tissues stimulates PP2A activity. Taken together, these findings show that adiponectin, derived from adipocytes, negatively regulates the invasiveness of breast cancer cells by activating the tumor suppressor PP2A.
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PMID:Adiponectin-activated AMPK stimulates dephosphorylation of AKT through protein phosphatase 2A activation. 1936 11

Both polyunsaturated fatty acids and AMPK promote energy partitioning away from energy consuming processes, such as fatty acid synthesis, towards energy generating processes, such as beta-oxidation. In this report, we demonstrate that arachidonic acid activates AMPK in primary rat hepatocytes, and that this effect is p38 MAPK-dependent. Activation of AMPK mimics the inhibition by arachidonic acid of the insulin-mediated induction of G6PD. Similar to intracellular signaling by arachidonic acid, AMPK decreases insulin signal transduction, increasing Ser(307) phosphorylation of IRS-1 and a subsequent decrease in AKT phosphorylation. Overexpression of dominant-negative AMPK abolishes the effect of arachidonic acid on G6PD expression. These data suggest a role for AMPK in the inhibition of G6PD by polyunsaturated fatty acids.
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PMID:A role for AMPK in the inhibition of glucose-6-phosphate dehydrogenase by polyunsaturated fatty acids. 1964 64

We have previously reported that adenoviral-mediated delivery of cytochrome P-450 (CYP) 4A2, which catalyzes the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE), results in endothelial dysfunction and hypertension in Sprague-Dawley (SD) rats (Wang JS, Singh H, Zhang F, Ishizuka T, Deng H, Kemp R, Wolin MS, Hintze TH, Abraham NG, Nasjletti A, Laniado-Schwartzman M. Circ Res 98: 962-969, 2006). In this study, we targeted the vascular endothelium by using a lentivirus construct expressing CYP4A2 under the control of the endothelium-specific promoter VE-cadherin (VECAD-4A2) and examined the effect of long-term CYP4A2 overexpression on blood pressure and kidney function in SD rats. A bolus injection of VECAD-4A2 increased blood pressure (P < 0.001) by 26, 36, and 30 mmHg 10, 20, and 30 days postinjection, respectively. Arteries from VECAD-4A2-transduced rats produced increased levels of 20-HETE (P < 0.01), expressed lower levels of endothelial nitric oxide synthase (eNOS) and phosphorylated eNOS (p-eNOS) (P < 0.05), generated higher levels of superoxide anion, and displayed decreased relaxing responsiveness to acetylcholine (P < 0.05). Proteinuria increased by twofold in VECAD-4A2-transduced rats compared with controls. Treatment of VECAD-4A2-transduced rats with HET0016, an inhibitor of 20-HETE biosynthesis, not only attenuated the increase in blood pressure (P < 0.05) but also improved vascular function (acetylcholine-induced relaxations) and reduced plasma creatinine and proteinuria. HET0016 treatment decreased oxidative stress and increased the phosphorylated state of key proteins that regulate endothelial function, including eNOS, AKT, and AMPK. Collectively, these findings demonstrate that augmentation of vascular endothelial 20-HETE levels results in hypertension, endothelial dysfunction, and renal injury, which is offset by HET0016 through a reduction in vascular 20-HETE coupled with a lessening of oxidative stress and the amplification of pAKT, pAMPK, and p-eNOS levels leading to normalization of endothelial responses.
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PMID:Endothelial-specific CYP4A2 overexpression leads to renal injury and hypertension via increased production of 20-HETE. 1967 80


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