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)

Although ethanol is known to sensitize hepatocytes to tumor necrosis factor (TNF) lethality, the mechanisms involved remain controversial. Recently, others have shown that adding TNFalpha to cultures of ethanol-pretreated hepatocytes provokes the mitochondrial permeability transition, cytochrome c release, procaspase 3 activation, and apoptosis. Although this demonstrates that ethanol can sensitize hepatocytes to TNF-mediated apoptosis, the hepatic inflammation and ballooning hepatocyte degeneration that typify alcohol-induced liver injury suggest that other mechanisms might predominate in vivo. To evaluate this possibility, acute responses to lipopolysaccharide (LPS), a potent inducer of TNFalpha, were compared in mice that had been fed either an ethanol-containing or control diet for 5 weeks. Despite enhanced induction of cytokines such as interleukin (IL)-10, IL-15, and IL-6 that protect hepatocytes from apoptosis, ethanol-fed mice exhibited a 4-5-fold increase in serum alanine aminotransferase after LPS, confirming increased liver injury. Six h post-LPS histology also differed notably in the two groups, with control livers demonstrating only scattered apoptotic hepatocytes, whereas ethanol-exposed livers had large foci of ballooned hepatocytes, inflammation, and scattered hemorrhage. No caspase 3 activity was noted during the initial 6 h after LPS in ethanol-fed mice, but this tripled by 1.5 h after LPS in controls. Procaspase 8 cleavage and activity of the apoptosis-associated kinase, Jun N-terminal kinase, were also greater in controls. In contrast, ethanol exposure did not inhibit activation of cytoprotective mitogen-activated protein kinases and AKT or attenuate induction of the anti-apoptotic factors NF-kappaB and inducible nitric oxide synthase. Consistent with these responses, neither cytochrome c release, an early apoptotic response, nor hepatic oligonucleosomal DNA fragmentation, the ultimate consequence of apoptosis, was increased by ethanol. Thus, ethanol exacerbates TNF-related hepatotoxicity in vivo without enhancing caspase 3-dependent apoptosis.
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PMID:Chronic ethanol exposure potentiates lipopolysaccharide liver injury despite inhibiting Jun N-terminal kinase and caspase 3 activation. 1181 69

IL-6 is an established growth factor for multiple myeloma tumor cells, stimulating proliferative and survival responses. Recent work indicates that IL-6 can activate the AKT kinase in myeloma cells. Thus, to test a potential role for AKT in IL-6-induced cellular responses, we transfected myeloma cell lines with an active 'E40K' or dominant negative'PH AKT construct using an adenoviral vector. Transfection of the E40K into myeloma cells resulted in enhanced tumor cell growth and expression of the PH dominant negative AKT resulted in both inhibition of the IL-6-dependent proliferative response and a decrease in S phase distribution. While transfection of E40K protected myeloma cells from dexamethasone-induced apoptosis, the dominant negative PH had no effect on the ability of IL-6 to protect these cells from dexamethasone. These results clearly demonstrate that AKT activation is critical for the IL-6 proliferative response. In addition, although the level of AKT activation can regulate sensitivity to dexamethasone-induced apoptosis, additional cytokine-induced AKT-independent pathways can mediate IL-6 protection against dexamethasone. DOI: 10.1038/sj/onc/1205194
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PMID:Role of the AKT kinase in expansion of multiple myeloma clones: effects on cytokine-dependent proliferative and survival responses. 1185 82

Farnesyl transferase inhibitors (FTIs) are anticancer agents designed to target ras processing and ras-dependent signal pathways. Because oncogenic ras mutations are found in up to 50% of multiple myeloma (MM) specimens, these agents may be effective in this disease. However, some preclinical studies suggest that FTI antitumor responses are unrelated to effects on ras. To address this issue in myeloma, we used the ANBL-6 myeloma cell line where interleukin (IL)-6-dependent cells are stably transfected with mutated N-ras or K-ras genes. Because expression of mutated ras allows for IL-6-independent growth, this is a good model to test whether FTIs specifically target growth-promoting ras-activated pathways in myeloma. Although they had little effect in 10% serum, two separate FTIs induced apoptosis of myeloma cells when cultured in low serum, and mutated ras-expressing cells were more sensitive than wild-type (WT) ras-expressing cells. However, induction of apoptosis did not correlate with inhibition of ras processing. Although they had no effect on AKT activity, under low serum conditions FTIs inhibited constitutive activation of the p70S6kinase and nuclear factor kappaB signal proteins in both mutated ras-expressing MM lines and extracellular signal-regulated kinase (ERK) activity in mutated N-ras-expressing cells. However, in studies where p70, nuclear factor kappaB, and ERK were comparably inhibited by other inhibitors or by gene transfer, we could not identify effects on these pathways as participating in the apoptotic response. FTIs were also able to abrogate the IL-6 proliferative response of WT ras-expressing MM cells, and this was associated with inhibition of IL-6-induced activation of ERK, AKT, and p70. The induction of apoptosis and prevention of the IL-6 response in MM cells containing mutated or WT ras provide support for the therapeutic potential of FTIs in this disease.
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PMID:Cytoreductive effects of farnesyl transferase inhibitors on multiple myeloma tumor cells. 1281 36

Since the first identification of interleukin (IL)-6 as a myeloma cell growth factor by Dr. Kawano's and Dr. Klein's groups 14 years ago, numerous studies have emphasized its major roles in the emergence of malignant plasma cells in vivo and in the generation of normal plasma cells. Four transcription factors control B-cell differentiation into plasma cells. The B-cell transcription factor pax-5 is mainly responsible for a B-cell phenotype, and bcl-6 represses the plasma cell transcription factor blimp-1 and plasma cell differentiation. bcl-6 expression is triggered by CD40 and IL-4 activation. A lack of CD40 and IL-4 activation yields a down-regulation of bcl-6 expression, and IL-6 stimulation yields an up-regulation of blimp-1, mainly through STAT3 activation. Blimp-1 further down-regulates bcl-6 and pax-5 expression and makes plasma cell differentiation possible. IL-6 as well as IL-10 up-regulate XBP-1. XBP-1 is another transcription factor that is involved in plasma cell differentiation and whose gene expression is shut down by pax-5. The plasma cell transcription factors blimp-1 and XBP-1 are up-regulated, and the B-cell transcription factors bcl-6 and pax-5 are down-regulated, in malignant cells compared to B-cells. Apart from the recent identification of these 4 transcription factors, the factors involved in normal plasma cell generation are mostly unknown. Regarding malignant plasma cells, 3 categories of growth factors have been identified: (1) the IL-6 family cytokines, IL-10, and interferon alpha that activate the Janus kinase-signal transducer and activator of transcription (JAK/STAT) and mitogen-activated protein (MAP) kinase pathways; (2) growth factors activating the phosphatidylinositol (PI)-3 kinase/AKT and MAP kinase pathways, unlike the JAK/STAT pathway (insulin-like growth factor 1, hepatocyte growth factor, and members of the epidermal growth factor family able to bind syndecan-1 proteoglycan); and (3) B-cell-activating factor (BAFF) or proliferation-inducing ligand (APRIL) that activate the nuclear factor KB and PI-3 kinase/AKT pathways. BAFF and APRIL bind to BAFF receptor and TACI and are major B-cell survival factors. Recent data indicate that these various growth factors may cooperate to provide optimum signaling because they are localized together and with cytoplasmic transduction elements in caveolinlinked membrane caveolae. The identification of these myeloma cell growth factors and of the associated transduction pathways should provide novel therapeutic targets in multiple myeloma.
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PMID:Survival and proliferation factors of normal and malignant plasma cells. 1295 3

The calcium-independent mannose 6-phosphate receptor (CIMPR) is a receptor for multiple ligands, including leukemia inhibitory factor (LIF), an IL-6 type cytokine, and IGF-II. CIMPR targets newly synthesized ligands to lysosomes and induces internalization/degradation of secreted ligands. A natural soluble form of CIMPR (sCIMPR) neutralizes IGF-II mitogenic potency on hepatocytes and fibroblasts. Herein we show that sCIMPR also inhibits LIF-driven proliferation of myeloid and lymphoid cell lines. Similar inhibition was observed with IL-6 and IL-11, two other IL-6-type cytokines that do not interact with CIMPR. Neutralizing anti-IGF-II antibodies inhibited IL-6-, IL-11-, and LIF-driven cell proliferation to the same extent as sCIMPR, suggesting that neutralization of serum IGF-II by sCIMPR plays a major role in IL-6-type cytokine-dependent cell proliferation. Confirming this idea, ERK1/2 and AKT/protein kinase B, the kinases necessary for cell proliferation and survival, were activated by IGF-II alone or by the association of IL-6-type cytokines and IGF-II. IL-6-type cytokines alone (up to 10 ng/ml) did not activate ERK1/2 or AKT, but did activate STAT3 (signal transducer and activator of transcription 3), a transcription factor necessary for the G1 to S phase cell cycle transition. Activation of ERK1/2 and AKT by IGF-II thus appears essential to sustain cellular expansion driven by IL-6-type cytokines.
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PMID:Soluble mannose 6-phosphate/insulin-like growth factor II (IGF-II) receptor inhibits interleukin-6-type cytokine-dependent proliferation by neutralization of IGF-II. 1295 77

Interleukin-6 (LI-6) is a known growth and survival factor in multiple myeloma via activation of extracellular signal-regulated kinase and phosphatidylinositol 3-kinase signaling cascade. In this report we show that Grb2-associated binder (Gab) family adapter proteins Gab1 and Gab2 are expressed by multiple myeloma cells; and that interleukin-6 induces their tyrosine phosphorylation and association with downstream signaling molecules. We further demonstrate that these events are Src family tyrosine kinase-dependent and specifically identify the role of hematopoietic cell kinase (Hck) as a new Gab family adapter protein kinase. Conversely, inhibition of Src family tyrosine kinases by the pyrazolopyrimidine PP2, as in kinase-inactive Hck mutants, significantly reduces IL-6-triggered activation of extracellular signal-regulated kinase and AKT-1, leading to significant reduction of multiple myeloma cell proliferation and survival. Taken together, these results delineate a key role for Hck-mediated phosphorylation of Gab1 and Gab2 docking proteins in IL-6-induced proliferation and survival of multiple myeloma cells and identify tyrosine kinases and downstream adapter proteins as potential new therapeutic targets in multiple myeloma.
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PMID:Critical role for hematopoietic cell kinase (Hck)-mediated phosphorylation of Gab1 and Gab2 docking proteins in interleukin 6-induced proliferation and survival of multiple myeloma cells. 1501 Apr 62

The IL-6-induced activation of the phosphatidylinositol-3' kinase (PI3-K)/AKT cascade in multiple myeloma (MM) cells is critical for tumor cell proliferation and viability. Since the IL-6 receptor does not contain binding sites for the p85 regulatory portion of PI3-K, intermediate molecules must play a role. Coimmunoprecipitation studies in MM cell lines demonstrated the IL-6-induced formation of two independent PI3-K-containing complexes: one containing p21 RAS but not STAT-3 and a second containing STAT-3 but not RAS. Both complexes demonstrated IL-6-induced lipid kinase activity. IL-6 also generated kinase activity in a mutant p110 molecule that could not bind p85. Use of dominant-negative (DN) constructs confirmed the presence of two independent pathways of activation: a DN RAS prevented the IL-6-induced generation of lipid kinase activity in the mutant p110 molecule but had no effect on activity generated in the STAT-3-containing complex. In contrast, a DN p85 prevented the generation of kinase activity in the STAT-3-containing complex but had no effect on activity generated in the p110 molecule. Both DN constructs significantly prevented the IL-6-induced activation of AKT. MM cells expressing activating RAS mutations demonstrated enhanced IL-6-independent growth and constitutive PI3-K activity. These data indicate two potential independent pathways of PI3-K/AKT activation in MM cells: one mediated via signaling through RAS which is independent of p85 and a second mediated via p85 and due to a STAT-3-containing complex.
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PMID:Interleukin-6 activates phosphoinositol-3' kinase in multiple myeloma tumor cells by signaling through RAS-dependent and, separately, through p85-dependent pathways. 1502 14

Ionizing or ultraviolet radiation-induced cellular survival signaling pathways induce development of cancer and insensitivity of tumor cells to radiation therapy. Accumulating evidence suggests that the phosphatidylinositide 3-kinase (PI3K)/AKT signal pathway is a major contributor to radioresistance. In many cell types PI3K/AKT signaling is a key cytoprotective response downstream of the EGFR family receptors and mediated carcinogenesis. Cytokines, such as HGF, IGF-I, and IL-6 also protects cells against apoptosis induced by radiation through PI3K/AKT pathway. The mechanics by which PI3K/AKT signaling functions in radiation responses may include its regulation of mitochondrial proteins, transcription factors, translation machinery, and cell-cycle progression. In addition, cross-talk between the PI3K/AKT pathway and mitogen-activated protein kinases, protein kinase A, and protein kinase C signal pathway may also play an important role.
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PMID:Phosphatidylinositide 3-kinase/AKT in radiation responses. 1516 54

Immunosuppressive factors, such as vascular endothelial growth factor, transforming growth factor-beta, prostaglandin E2, interleukin (IL)-10, and IL-6, are made frequently by cancer cells. These factors, along with others, can inhibit the development and function of tumor-reactive effector T cells and the clinical results of cancer vaccines. Production of these factors by tumor cells is associated with disease progression and may represent an active immune surveillance escape mechanism. However, a number of factors appear to be made directly in response to signaling molecules, such as RAS, AKT, and signal transducer and activator of transcription 3, which are activated as a result of genetic events that occur during oncogenesis. Methods to overcome the negative effects of immunosuppressive factors, which are "hard wired" into gene programs of cancer cells, might then improve the results of cancer vaccines. For example, specific blocking antibodies, which recognize such factors, or kinase inhibitors, which block the signaling pathways that lead to their production, could potentially be used as vaccine adjuvants. The effects of immunosuppressive factors may also be "turned off" by cytokines with tumor suppressor properties. The enhanced clinical and immunological effects of melanoma vaccines observed after the administration of high doses of interferon-alpha2b provide a "proof of principle" in human patients, that agents which counter the gene programs of cancer cells, causing them to intrinsically resist tumor-reactive T cells, may improve significantly the efficacy of cancer vaccines.
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PMID:Amplifying cancer vaccine responses by modifying pathogenic gene programs in tumor cells. 1527 80

IL-6 has been reported to play a central role in growth and survival of multiple myeloma (MM) cells. However, recently we have demonstrated that in the presence of bone marrow stromal cells, survival of MM cells becomes independent of the IL-6/gp130/STAT3 pathway questioning the singular role of IL-6 in MM. Therefore, it was the aim of this study to identify additional factors and signaling pathways that might contribute to the growth and survival of MM cells. We found that in addition to IL-6 a number of bone marrow derived cytokines such as LIF, VEGF, bFGF, MIP-1alpha, SDF-1alpha, IL-1beta, SCF and IL-3 activate the MAPK pathway and induce proliferation of MM.1S and RPMI-8226 MM cells. In addition, these cytokines independently phosphorylate the forkhead family member FKHR via PI3-K/AKT and support survival of primary human MM cells. Inhibition of these pathways induces apoptosis in MM cell lines and primary MM cells. Thus, we provide evidence that in addition to IL-6 a number of different factors trigger important growth-promoting pathways to support the proliferation and survival of MM cells. Therefore, blocking such pathways, rather than blocking a single factor, might be a promising approach for the development of novel treatment strategies in MM.
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PMID:PI3-K/AKT/FKHR and MAPK signaling cascades are redundantly stimulated by a variety of cytokines and contribute independently to proliferation and survival of multiple myeloma cells. 1535 48


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