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)

Hematopoietic stem cells (HSCs) reside in the bone marrow (BM) niche in a noncycling state and enter the cell cycle at long intervals. This unique property of HSCs is reminiscent of hibernation in mammals. However, little is known about inter- and intracellular signaling mechanisms underlying this unique property of HSCs. This is largely due to the paucity of HSCs making application of traditional signal transduction assays difficult. To address these issues, we have developed a novel assay based on in-droplet single-cell staining and quantitative fluorescence imaging analysis. Using this assay system, we demonstrate that freshly isolated HSCs from the BM niche lack lipid raft clustering, exhibit repression of the AKT-FOXO signaling pathway, and express abundant p57(Kip2) cyclin-dependent kinase inhibitor. Lipid raft clustering induced by cytokines was essential for HSC re-entry into the cell cycle. Conversely, inhibition of lipid raft clustering caused sustained nuclear accumulation of FOXO transcription factors and induced HSC hibernation ex vivo. Among niche signals examined, transforming growth factor-beta (TGF-beta) efficiently inhibited lipid raft clustering and induced p57(Kip2) expression, leading to HSC hibernation. These data uncover a critical role for lipid rafts in HSC fate decision and establish the role of TGF-beta as a niche signal in control of HSC hibernation in the BM niche.
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PMID:Cytokine signaling, lipid raft clustering, and HSC hibernation. 1744 72

Smad proteins are intracellular transducers for transforming growth factor-beta (TGF-beta) signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-beta and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3beta protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3beta (GSK-3beta), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB(Ser133) protein levels, an enhanced interaction between pCREB(Ser133) and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.
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PMID:Lithium inhibits Smad3/4 transactivation via increased CREB activity induced by enhanced PKA and AKT signaling. 1807 82

Mesenchymal stem cells (MSCs) are multipotent cells capable of developing along the chondrogenic, osteogenic and adipogenic lineages. As such, they have received interest as a potential cell source for tissue engineering strategies. Cartilage is an avascular tissue and thus resides in a microenvironment with reduced oxygen tension. The aim of this study was to examine the effect of a low oxygen environment on MSC differentiation along the chondrogenic route. In MSCs exposed to chondrogenic growth factors, transforming growth factor-beta and dexamethasone, in a hypoxic environment (2% oxygen), the induction of collagen II expression and proteoglygan deposition was significantly greater than that observed when cells were exposed to the chondrogenic growth factors under normoxic (20% oxygen) conditions. The transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha), is a crucial mediator of the cellular response to hypoxia. Following exposure of MSCs to hypoxia (2% oxygen), HIF-1alpha translocated from the cytosol to the nucleus and bound to its target DNA consensus sequence. Similarly, hypoxia evoked an increase in phosphorylation of both AKT and p38 mitogen activated protein kinase, upstream of HIF-1alpha activation. Furthermore, the PI3 kinase/AKT inhibitor, LY294002, and p38 inhibitor, SB 203580, prevented the hypoxia-mediated stabilisation of HIF-1alpha. To assess the role of HIF-1alpha in the hypoxia-induced increase in chondrogenesis, we employed an siRNA knockdown approach. In cells exposed to HIF-1alpha siRNA, the hypoxia-induced enhancement of chondrogenesis, as evidenced by upregulation of collagen II, sox-9 and proteoglycan deposition, was absent. This provides evidence for HIF-1alpha being a key mediator of the beneficial effect of a low oxygen environment on chondrogenesis.
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PMID:Hypoxia promotes chondrogenesis in rat mesenchymal stem cells: a role for AKT and hypoxia-inducible factor (HIF)-1alpha. 1836 89

Prostate cancer is a highly heterogenous disease in which a patient-tailored care program is much desired. Central to this goal is the development of novel targeted pharmacological interventions. To develop these treatment strategies, an understanding of the integration of cellular pathways involved in both tumorigenesis and tumor suppression is crucial. Of further interest are the events elicited by drug treatments that exploit the underlying molecular pathology in cancer. This review briefly describes the evidence that suggests integration of three established pathways: the tumorigenic phosphoinositide 3-kinase/protein kinase B (AKT) pathway, the tumor suppressive phosphatase and tensin homolog deleted on chromosome 10 pathway, and the tumor suppressive transforming growth factor-beta pathway. More importantly, we discuss novel pharmaceutical agents that target key points of integration in these three pathways. These new therapeutic strategies include the use of agents that target iron to inhibit proliferation via multiple mechanisms and suppression of AKT by cytosolic phospholipase A(2)-alpha inhibitors.
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PMID:Pharmacological targeting of the integrated protein kinase B, phosphatase and tensin homolog deleted on chromosome 10, and transforming growth factor-beta pathways in prostate cancer. 1905 70

Hepatocellular carcinoma (HCC) is a major health problem, being the sixth most common cancer world-wide. Dysregulation of the balance between proliferation and cell death represents a pro-tumorigenic principle in human hepatocarcinogenesis. This review updates the recent relevant contributions reporting molecular alterations for HCC that induce an imbalance in the regulation of apoptosis. Alterations in the expression and/or activation of p53 are frequent in HCC cells, which confer on them resistance to chemotherapeutic drugs. Many HCCs are also insensitive to apoptosis induced either by death receptor ligands, such as FasL or TRAIL, or by transforming growth factor-beta (TGF-beta). Although the expression of some pro-apoptotic genes is decreased, the balance between death and survival is dysregulated in HCC mainly due to overactivation of anti-apoptotic pathways. Indeed, some molecules involved in counteracting apoptosis, such as Bcl-X(L), Mcl-1, c-IAP1, XIAP or survivin are over-expressed in HCC cells. Furthermore, some growth factors that mediate cell survival are up-regulated in HCC, as well as the molecules involved in the machinery responsible for cleavage of their pro-forms to an active peptide. The expression and/or activation of the JAK/STAT, PI3K/AKT and RAS/ERKs pathways are enhanced in many HCC cells, conferring on them resistance to apoptotic stimuli. Finally, recent evidence indicates that inflammatory processes, as well as the epithelial-mesenchymal transitions that occur in HCC cells to facilitate their dissemination, are related to cell survival. Therefore, therapeutic strategies to selectively inhibit anti-apoptotic signals in liver tumor cells have the potential to provide powerful tools to treat HCC.
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PMID:Dysregulation of apoptosis in hepatocellular carcinoma cells. 1919 51

Among the many oncogenic variants of the anaplastic lymphoma kinase (ALK), nucleophosmin 1 (NPM)/ALK fusion protein expressed in the subset of T-cell lymphoma (ALK(+)TCL) is currently the best characterized. NPM/ALK activates several signal transduction pathways, including PI3K/AKT, MEK/ERK, mTORC1, STAT3, and STAT5b. In turn, the pathways modulate expression and function of many genes and proteins involved in the key cellular functions such as proliferation, growth, survival, metabolism, and angiogenesis. Recent data indicate that NPM/ALK also promotes immune evasion of the ALK(+)TCL by inducing through STAT3 activation the expression of immunosuppressive cytokines interleukin-10 (IL-10) and transforming growth factor-beta (TGFss) and cell surface protein CD274 (PD-L1, B7-H1). In addition, NPM/ALK protects its own expression by mediating via STAT3 and at least one member of the DNA methyltransferase family DNMT1 epigenetic silencing of the SHP-1 and STAT5a genes. In ALK+TCL cells, SHP-1 and STAT5a proteins act as potent tumor suppressors by promoting degradation of the NPM/ALK protein and inhibiting expression of the NPM/ALK gene, respectively. These findings provide further rationale to therapeutically target ALK and its effector proteins, foremost STAT3. They also suggest that immunotherapeutic approaches to ALK(+)TCL and, possibly, other ALK-driven malignancies may require inhibition of ALK and STAT3 to achieve the optimal clinical efficacy.
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PMID:Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches. 1939 33

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease, and prior attempts to develop genomic-based classification for HCC have yielded highly divergent results, indicating difficulty in identifying unified molecular anatomy. We performed a meta-analysis of gene expression profiles in data sets from eight independent patient cohorts across the world. In addition, aiming to establish the real world applicability of a classification system, we profiled 118 formalin-fixed, paraffin-embedded tissues from an additional patient cohort. A total of 603 patients were analyzed, representing the major etiologies of HCC (hepatitis B and C) collected from Western and Eastern countries. We observed three robust HCC subclasses (termed S1, S2, and S3), each correlated with clinical parameters such as tumor size, extent of cellular differentiation, and serum alpha-fetoprotein levels. An analysis of the components of the signatures indicated that S1 reflected aberrant activation of the WNT signaling pathway, S2 was characterized by proliferation as well as MYC and AKT activation, and S3 was associated with hepatocyte differentiation. Functional studies indicated that the WNT pathway activation signature characteristic of S1 tumors was not simply the result of beta-catenin mutation but rather was the result of transforming growth factor-beta activation, thus representing a new mechanism of WNT pathway activation in HCC. These experiments establish the first consensus classification framework for HCC based on gene expression profiles and highlight the power of integrating multiple data sets to define a robust molecular taxonomy of the disease.
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PMID:Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. 1972 56

Most members of the tumor-necrosis factor superfamily have been reported to mediate reverse signaling in T cells, macrophages, and/or dendritic cells. BAFF has been reported to have important functions in B-cell survival through forward signaling, but the presence of reverse signaling has not been explored. To investigate the possibility of BAFF-mediated reverse signaling, the expression patterns and functions of BAFF were analyzed in monocytic cell lines including the human macrophage-like cell line, THP-1. The expression of BAFF and its receptors was detected in monocytic cell lines, either before or after activation. The stimulation of BAFF induced the expression of matrix metalloproteinase (MMP)-9, interleukin -8, and transforming growth factor-beta-induced gene product (beta ig-h3) and the upregulation of intercellular adhesion molecule-1 in THP-1 cells. The activation of mitogen-activated protein kinase extracellular signal-regulated kinase1/2 and nuclear factor-kappaB was required for these responses. In addition to these stimulatory effects, BAFF-mediated signaling inhibited processes involving cytoskeletal movement such as phagocytosis and transmigration through blocking the activation of phosphatidylinositol 3-kinase/AKT and Rac-1. Furthermore, murine primary macrophage culture such as peritoneal macrophages expressed BAFF and stimulation of it induced the expression of MMP-9. These observations show that the reverse signaling initiated from BAFF induces the expression of inflammatory mediators while suppressing the cytoskeletal movements associated with phagocytosis and transmigration.
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PMID:Reverse signaling through BAFF differentially regulates the expression of inflammatory mediators and cytoskeletal movements in THP-1 cells. 1984 39

The identification of genes involved in carcinogenesis and tumor progression is of great interest since these genes might be feasible as candidates for new tumor-targeted therapy strategies. Chimeric tumor suppressor-1 (CTS-1), an artificial synthetic variant of p53, resists common p53 inactivation and could therefore be defined as a dominant-positive p53 variant. Overexpression of CTS-1 induces caspase-independent cell death. We used whole-genome microarray expression analysis in a parental (229(P)) and a CTS-1-resistant glioma cell line (229(Res)) to analyze alterations in gene expression in Ad-CTS-1-infected and in uninfected parental and resistant cells. In total, 700 genes were differentially expressed in infected and 313 genes in uninfected 229(Res) versus 229(P) cells. Ingenuity Pathway Analysis determined a variety of differentially expressed genes in Ad-CTS-1-infected cells that were members of intracellular networks with central tumor-involved players such as nuclear factor-kappaB (NFkappaB), protein kinase B/AKT or transforming growth factor-beta. Here we focused on the function of NFkappaB in Ad-CTS-1-mediated cell death in glioma. NFkappaB was activated in Ad-CTS-1-infected 229(P) but not 229(Res) cells. NFkappaB activation was accompanied by the induction of cell death in parental cells. Inhibition of NFkappaB activity by expression of an IkappaB super repressor or upregulation of the NFkappaB-linked gene Bex protected parental cells to Ad-CTS-1-induced cell death, whereas knockdown of Bex sensitized both parental and resistant cells. Taken together, these data suggest that activation of the normally antiapoptotic protein NFkappaB does not always necessarily protect cells from apoptosis but, in the glioma cell lines tested so far, and in an environment where p53 is constitutively active, also leads to the induction of cell death.
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PMID:Gene expression profile in a glioma cell line resistant to cell death induced by the chimeric tumor suppressor-1 (CTS-1), a dominant-positive variant of p53--the role of NFkappaB. 2001 65

A20 or tumor necrosis factor-induced protein 3 is a negative regulator of nuclear factor kappaB signaling. A20 has been shown previously to attenuate cardiac hypertrophy in vitro and postmyocardial infarction remodeling in vivo. In the present study, we tested the hypothesis that overexpression of A20 in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human A20 expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding in A20 transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by echocardiography, as well as by pathological and molecular analyses of heart samples. Constitutive overexpression of human A20 in the murine heart attenuated the hypertrophic response and markedly reduced inflammation, apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased A20 levels in response to hypertrophic stimuli. Western blot experiments further showed A20 expression markedly blocked transforming growth factor-beta-activated kinase 1-dependent c-Jun N-terminal kinase/p38 signaling cascade but with no difference in either extracellular signal-regulated kinase 1/2 or AKT activation in vivo and in vitro. In cultured neonatal rat cardiac myocytes, [3H]proline incorporation and Western blot assays revealed that A20 expression suppressed transforming growth factor-beta-induced collagen synthesis and transforming growth factor-beta-activated kinase 1-dependent Smad 2/3/4 activation. In conclusion, A20 improves cardiac functions and inhibits cardiac hypertrophy, inflammation, apoptosis, and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling.
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PMID:Tumor suppressor A20 protects against cardiac hypertrophy and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling. 2058 9


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