Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress

Zundel, Wayne; Giaccia, Amato J.

doi:10.1101/gad.12.13.1941

Cited by 195 publications

(148 citation statements)

References 37 publications

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“…Moreover researchers have used labeled PH domains as a means of measuring 3-phosphoinositide generation in vivo (34,35), suggesting that C 2 -ceramide was probably blocking the activation of PI 3-kinase or the accumulation of PI(3,4)P 2 or PI(3,4,5)P 3 . Although others and we have demonstrated that C 2 -ceramide has no effect on PI 3-kinase in NIH-3T3 fibroblasts or 3T3-L1 adipocytes (9, 10, 13, 15, 22, 36 -39), contradicting reports have suggested that C 2 -ceramide potently inhibits PI 3-kinase activation (11,40,41). To confirm that the effects of C 2 -ceramide did not result from its inhibition of PI 3-kinase we evaluated whether C 2 -ceramide blocked activation of Akt/PKB triggered by directly introducing PI(3,4,5)P 3 into intracellular domains.…”

Section: Ceramide Blocks the Effects Of Insulin On Both The Ph Domainmentioning

confidence: 66%

“…2 In the majority of studies (9, 10, 15, 38 -40), 2 but not all (11,40,41), ceramide analogs were shown to have no effect on hormone-stimulated PI 3-kinase. Moreover others and we have demonstrated previously that ceramide does not inhibit 3Ј-phosphoinositide production by insulin or other hormonal agonists (14,22).…”

Section: Overexpression Of the Sv40 Small T Antigen Prevents The Inhimentioning

confidence: 99%

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Regulation of Insulin Action by Ceramide

Stratford

Hoehn

Liu

et al. 2004

Journal of Biological Chemistry

344

118

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The sphingolipid ceramide negatively regulates insulin action by inhibiting Akt/protein kinase B (PKB), a serine/threonine kinase that is a central regulator of glucose uptake and anabolic metabolism. Despite considerable attention, the molecular mechanism accounting for this action of ceramide has remained both elusive and controversial. Herein we utilized deletion constructs encoding two different functional domains of Akt/PKB to identify which region of the enzyme conferred responsiveness to ceramide. Surprisingly the findings obtained with these separate domains reveal that ceramide blocks insulin stimulation of Akt/PKB by two independent mechanisms. First, using the isolated pleckstrin homology domain, we found that ceramide specifically blocks the translocation of Akt/PKB, but not its upstream activator phosphoinositide-dependent kinase-1, to the plasma membrane. Second, using a construct lacking this pleckstrin homology domain, which does not require translocation for activation, we found that ceramide stimulates the dephosphorylation of Akt/ PKB by protein phosphatase 2A. Collectively these findings identify at least two independent mechanisms by which excessive ceramide accumulation in peripheral tissues could contribute to the development of insulin resistance. Moreover the results obtained provide a unifying theory to account for the numerous dissenting reports investigating the actions of ceramide toward Akt/PKB.A strong correlation between intramyocellular lipid levels and the severity of insulin resistance has prompted investigators to hypothesize that insulin resistance results from the ectopic accumulation of fat in tissues other than adipose (1, 2). Specifically, many researchers have speculated that increased availability of lipids to peripheral tissues causes insulin resistance by promoting the accumulation of fat-derived metabolites capable of inhibiting insulin action (1, 2). Numerous recent studies support the hypothesis that the aberrant deposition of the sphingolipid ceramide in skeletal muscle and liver contributes to the development of insulin resistance resulting from lipid oversupply. First, insulin resistant rodents (3, 4) and humans (5, 6) have elevated ceramide levels in their peripheral tissues. Second, exercise training insulin-resistant rodents markedly improves their insulin sensitivity while substantially lowering intramuscular ceramide levels (7). Third, ceramide analogs or agents that induce endogenous ceramide accumulation inhibit insulin signaling and insulin-stimulated glycogen synthesis and glucose uptake (8 -14). Fourth, inhibitors of de novo ceramide synthesis prevent the antagonistic effects of saturated fatty acids on insulin signaling in cultured myotubes (9). The inhibitory effect of ceramides on insulin signaling result, at least partially, from their ability to block the phosphorylation and activation of Akt/protein kinase B, a serine/ threonine kinase that is a central mediator of many insulin effects (10, 15, 16). The studies described herein investigated the m...

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Section: Ceramide Blocks the Effects Of Insulin On Both The Ph Domainmentioning

confidence: 66%

Section: Overexpression Of the Sv40 Small T Antigen Prevents The Inhimentioning

confidence: 99%

Regulation of Insulin Action by Ceramide

Stratford

Hoehn

Liu

et al. 2004

Journal of Biological Chemistry

344

118

View full text Add to dashboard Cite

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“…Akt is an important anti-apoptotic protein through which survival signals suppress cell death induced by growth factor withdrawal, cell cycle discordance, and detachment of cells from their extracellular matrix, but its role in influencing cell fate during other conditions of stress has been more controversial. Several studies have reported that environmental stresses capable of inducing apoptosis, such as UVC, ionizing radiation (IR), and hyperosmotic stress lead to the downregulation of the PI3K/Akt pathway (Meier et al, 1998;Zhou et al, 1998;Zundel and Giaccia, 1998), and it has been suggested that such downregulation is important in the apoptotic process. However, Akt is activated in response to oxidant injury as well as several other stresses known to exert their cytotoxic effects in part through generation of ROS or perturbations in cellular redox status (Konishi et al, 1997;Sonoda et al, 1999;Klotz et al, 2000;Wang et al, 2000b;Huang et al, 2001).…”

Section: Pi3-kinase/akt Pathwaymentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,091

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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“…Interestingly, activation of PKB can be down-regulated by certain stress stimuli which increase intracellular ceramide [43,44]. Thus agents which activate acidic sphingomyelinase (such as tumour necrosis factor-α) may antagonize PKB activity.…”

Section: Phosphatidylinositol 3-kinase (Pi-3k) Mediates Pkb Activationmentioning

confidence: 99%

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

Coffer

Jin

Woodgett

1998

Biochemical Journal

988

818

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While a plethora of extracellular molecules exist that modulate cellular functions via binding to membrane receptors inside the cell, their actions are mediated by relatively few signalling mechanisms. One of these is activation of phosphatidylinositol 3-kinase (PI-3K), which results in the generation of a membranerestricted second messenger, polyphosphatidylinositides containing a 3h-phosphate. How these molecules transduced the effects of agonists of PI-3K was unclear until the recent discovery that several protein kinases become activated upon exposure to 3h-phosphorylated inositol lipids. These enzymes include protein kinase B (PKB)\AKT and PtdIns(3,4,5)P $ -dependent kinases 1 and 2, the first two of which interact with 3h-phosphorylated ORIGINS OF AKTThe AKR strain of mice exhibit a high incidence of leukaemias and lymphomas from spontaneous thymoma [1]. A retrovirus termed AKT8 was isolated from one of these lines derived from a spontaneous thymoma. This virus was demonstrated to uniquely transform only mink lung cells (CCL64) in culture, while virus inoculated into newborn mice was shown to be tumorigenic [2]. The non-viral DNA component transduced from the mouse genome was subsequently identified, and two human homologues, AKT1 and AKT2, cloned [3]. The location of the human AKT locus was mapped to chromosome 14q32, proximal to the immunoglobulin-heavy-chain locus [4], a region frequently affected by translocations and inversions in human Tcell leukaemia\lymphoma, mixed-lineage childhood leukaemia and clonal T-cell proliferations in ataxia telangiectasia, supporting a role for this oncogene in formation of a variety of tumours [5]. Analysis of a panel of human tumours revealed a 20-fold amplification of AKT1 in a primary gastric adenocarcinoma. AKT2, on the other hand, was mapped to chromosome region 19q13.1-q13.2 and shown to be amplified and overexpressed in several ovarian carcinoma and pancreatic cancer cell lines [6,7]. A recent large-scale study of AKT2 alterations in ovarian and breast tumours revealed amplification in 12.1 % ovarian and 2.8 % breast carcinomas [8]. Furthermore, amplification of AKT2 was especially frequent in undifferentiated tumours, suggesting that AKT2 alterations may be associated with tumour aggressiveness.Abbreviations used : PI-3K, phosphatidylinositol 3-kinase ; PKB, protein kinase B ; PKA, protein kinase A ; PKC, protein kinase C ; RAC-PK, related to A-and C-kinase ; PH, pleckstrin homology ; PtdIns, phosphoinositide ; PDGF, platelet-derived growth factor ; EGF, epidermal growth factor ; bFGF, basic fibroblast growth factor ; IL, interleukin ; ERK, extracellular-signal-regulated kinase ; Btk, Bruton tyrosine kinase ; PDK, PtdIns(3,4,5)P 3 -dependent kinase ; MAPKAP, mitogen-activated protein kinase-activated protein ; SH2, Src homology 2 ; gag, group-specific antigen ; GLUT, glucose transporter ; GSK, glycogen synthase kinase ; PFK2, 6-phosphofructose-2-kinase ; IGF, insulin-like growth factor ; 4E-BP1, 4E-binding protein ; PHAS, pH-and acid-stable ; BCR-ABL, breakpoint...

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Inhibition of the anti-apoptotic PI(3)K/Akt/Bad pathway by stress

Cited by 195 publications

References 37 publications

Regulation of Insulin Action by Ceramide

Regulation of Insulin Action by Ceramide

Cellular response to oxidative stress: Signaling for suicide and survival*

Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation

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