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Specific TrkA survival signals interfere with different apoptotic pathways
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of special interest. NGF, acting through its TrkA receptor, is able to protect cells from apoptosis induced by several stimuli, including c-Myc expression and UV radiation. This report shows that mutant TrkA receptors unable to stimulate Akt/PKB are defective in promoting protection from UV-radiation-induced apoptosis. However, this mutant receptor is still able to fully protect from c-Myc-induced apoptosis. These results suggest that NGF acting through TrkA receptor activates different intracellular survival pathways, one of them being P13K/Akt.
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of special interest Ulrich E, Duwel A, Kauffmann-Zeh A, Gilbert C, Lyon D, Rudkin B, Evan G, Martin-Zanca D. Specific TrkA survival signals interfere with different apoptotic pathways. Oncogene. 16:1998;825-832 NGF, acting through its TrkA receptor, is able to protect cells from apoptosis induced by several stimuli, including c-Myc expression and UV radiation. This report shows that mutant TrkA receptors unable to stimulate Akt/PKB are defective in promoting protection from UV-radiation-induced apoptosis. However, this mutant receptor is still able to fully protect from c-Myc-induced apoptosis. These results suggest that NGF acting through TrkA receptor activates different intracellular survival pathways, one of them being P13K/Akt.
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Oncogene
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Ulrich, E.1
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0030808984
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Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase
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of special interest. The activity of p38 kinase is undetectable in the presence of serum or survival factors, but increases following trophic factor withdrawal. Inhibition of p38 prevents apoptosis induced by survival factor withdrawal.
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of special interest Kummer JL, Rao PK, Heidenreich KA. Apoptosis induced by withdrawal of trophic factors is mediated by p38 mitogen-activated protein kinase. J Biol Chem. 272:1997;20490-20494 The activity of p38 kinase is undetectable in the presence of serum or survival factors, but increases following trophic factor withdrawal. Inhibition of p38 prevents apoptosis induced by survival factor withdrawal.
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Kummer, J.L.1
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0032076183
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Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the jaks in cytokine-induced biologic responses
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Roding SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, King KL, Sheehan KCF, Yin L, Pennica D, Johnson EM, Schreiber RD. Disruption of the Jak1 gene demonstrates obligatory and nonredundant roles of the jaks in cytokine-induced biologic responses. Cell. 93:1998;373-383.
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Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase
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of special interest. Active Akt/PKB is able to promote survival and delays cell death of growth factor starved BAF/3 cells. Expression of constitutive active forms of Akt/PKB induces Bcl-2 and c-myc expression.
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of special interest Ahmed NN, Grimes HL, Bellacosa A, Chan TO, Tsichlis P. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci USA. 94:1997;3627-3632 Active Akt/PKB is able to promote survival and delays cell death of growth factor starved BAF/3 cells. Expression of constitutive active forms of Akt/PKB induces Bcl-2 and c-myc expression.
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Tsichlis, P.5
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18
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0028286119
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V-rat suppresses apoptosis and promotes growth of interleukin-3-dependent myeloid cells
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Cleveland JL, Troppmair J, Packham G, Askew DS, Lloyd P, Gonzalez-Garcia M, Nunez G, Ihle JN, Rapp UR. v-rat suppresses apoptosis and promotes growth of interleukin-3-dependent myeloid cells. Oncogene. 9:1994;2217-2226.
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0031041317
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Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy
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of special interest. Cardiotrophin 1 (CT-1) is a potent survival signal for cardiac myocytes. CT-1 activates several transduction pathways, including MAP kinase. The protective ellect of CT-1 is blocked by MEK inhibitors, as well as by expression of dominant-negative MEK1.
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of special interest Sheng Z, Knowlton K, Chen J, Hoshijima M, Brown JH, Chien KR. Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. J Biol Chem. 272:1997;5783-5791 Cardiotrophin 1 (CT-1) is a potent survival signal for cardiac myocytes. CT-1 activates several transduction pathways, including MAP kinase. The protective ellect of CT-1 is blocked by MEK inhibitors, as well as by expression of dominant-negative MEK1.
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J Biol Chem
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Sheng, Z.1
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Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways
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Parrizas M, Saltiel AR, LeRoith D. Insulin-like growth factor 1 inhibits apoptosis using the phosphatidylinositol 3'-kinase and mitogen-activated protein kinase pathways. J Biol Chem. 272:1997;154-161.
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Parrizas, M.1
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Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis
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Horiuchi M, Hayashida W, Kambe T, Yamada T, Dzau VJ. Angiotensin type 2 receptor dephosphorylates Bcl-2 by activating mitogen-activated protein kinase phosphatase-1 and induces apoptosis. J Biol Chem. 272:1997;19022-19026.
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22
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0031850872
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Argos induces programmed cell death the developing Drosophila eye by inhibition of the Ras pathway
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of special interest. Argos is a diffusible inhibitor of the EGF-receptor and Ras pathway in Drosophila. Overexpression of Argos induces cell death in the developing eye. Expression of an activated version of Ras blocks Argos-induced apoptosis. In addition, gain-of-function mutations of MEK and Erk, that act downstream of Ras, suppress Hid-induced cell death.
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of special interest Sawamoto K, Taguchi A, Hirota Y, Yamada C, Jin M, Okano H. Argos induces programmed cell death the developing Drosophila eye by inhibition of the Ras pathway. Cell Death Differ. 5:1998;262-270 Argos is a diffusible inhibitor of the EGF-receptor and Ras pathway in Drosophila. Overexpression of Argos induces cell death in the developing eye. Expression of an activated version of Ras blocks Argos-induced apoptosis. In addition, gain-of-function mutations of MEK and Erk, that act downstream of Ras, suppress Hid-induced cell death.
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Sawamoto, K.1
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Wojnowski L, Zimmer AM, Beck TW, Hahn H, Bernal R, Rapp UR, Zimmer A. Endothelial apoptosis in Braf-deficient mice. Nat Genet. 16:1997;293-297.
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Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1
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Tanaka N, Ishihara M, Kitagawa M, Harada H, Kimura T, Matsuyama T, Lamphier MS, Aizawa S, Mak TW, Taniguchi T. Cellular commitment to oncogene-induced transformation or apoptosis is dependent on the transcription factor IRF-1. Cell. 77:1994;829-839.
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Tanaka, N.1
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Lamphier, M.S.7
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25
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0031028730
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Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB
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of outstanding interest. The oncogenic form of Ras proteins blocks c-myc-induced apoptosis. Ras proteins activate several signalling pathways, among them, the PI3K/Akt pathway seems responsible for the pro-survival effect. Surprisingly, activation of the Raf/MAPK pathway does not prevent apoptosis but enhances it.
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of outstanding interest Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J, Evan G. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature. 385:1997;544-548 The oncogenic form of Ras proteins blocks c-myc-induced apoptosis. Ras proteins activate several signalling pathways, among them, the PI3K/Akt pathway seems responsible for the pro-survival effect. Surprisingly, activation of the Raf/MAPK pathway does not prevent apoptosis but enhances it.
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Nature
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Kauffmann-Zeh, A.1
Rodriguez-Viciana, P.2
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Gilbert, C.4
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Downward, J.6
Evan, G.7
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26
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0030971576
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Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival
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Gunn-Moore FJ, Williams AG, Toms NJ, Tavare JM. Activation of mitogen-activated protein kinase and p70S6 kinase is not correlated with cerebellar granule cell survival. Biochem J. 324:1997;365-369.
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Pritchard, C.1
McMahon, M.2
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28
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0031053586
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Regulation of neuronal survival by the serine-threonine protein kinase Akt
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of outstanding interest. This is the first study showing that Akt mediates the anti-apoptotic effect of survival factors. Active forms of Akt prevent apoptosis of neurons induced by trophic factor withdrawal. Dominant-negative forms of Akt block the protective effect induced by IGF-1, suggesting that it prevents apoptosis by activation of Akt through PI3K.
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of outstanding interest Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME. Regulation of neuronal survival by the serine-threonine protein kinase Akt. Science. 275:1997;661-665 This is the first study showing that Akt mediates the anti-apoptotic effect of survival factors. Active forms of Akt prevent apoptosis of neurons induced by trophic factor withdrawal. Dominant-negative forms of Akt block the protective effect induced by IGF-1, suggesting that it prevents apoptosis by activation of Akt through PI3K.
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Science
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Dudek, H.1
Datta, S.R.2
Franke, T.F.3
Birnbaum, M.J.4
Yao, R.5
Cooper, G.M.6
Segal, R.A.7
Kaplan, D.R.8
Greenberg, M.E.9
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29
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0031923788
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Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line
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Eves EM, Xiong BW, Kennedy SG, Tsichlis PN, Rosner MR, Hay N. Akt, a target of phosphatidylinositol 3-kinase, inhibits apoptosis in a differentiating neuronal cell line. Mol Cell Biol. 18:1998;2143-2152.
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Eves, E.M.1
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Kennedy, S.G.3
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Hay, N.6
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30
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The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal
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of outstanding interest. Akt/PKB blocks apoptosis in Rat1a fibroblasts induced by c-myc expression in the absence of serum. Importantly, expression of active forms of Akt/PKB do not alter Bcl-2 or Bcl-XL expression, but block caspase activation
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of outstanding interest Kennedy SG, Wagner AJ, Conzen SD, Jodan J, Bellacosa A, Tsichlis PN, Hay N. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 11:1997;701-713 Akt/PKB blocks apoptosis in Rat1a fibroblasts induced by c-myc expression in the absence of serum. Importantly, expression of active forms of Akt/PKB do not alter Bcl-2 or Bcl-XL expression, but block caspase activation.
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Genes Dev
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Bellacosa, A.5
Tsichlis, P.N.6
Hay, N.7
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Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase
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Lores P, Morin L, Luna R, Gacon G. Enhanced apoptosis in the thymus of transgenic mice expressing constitutively activated forms of human Rac2GTPase. Oncogene. 15:1997;601-605.
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Oncogene
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Rho regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but bcl2 dependent pathway
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in press
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Esteve P, Embade N, Perona R, Jimenez B, del Peso L, Leon J, Arendes M, Miki T, Lacal JC. Rho regulated signals induce apoptosis in vitro and in vivo by a p53-independent, but bcl2 dependent pathway. Oncogene. 1998;. in press.
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Oncogene
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Esteve, P.1
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Perona, R.3
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Leon, J.6
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34
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0030803278
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Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153
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Brenner B, Koppenhoefer U, Weinstock C, Linderkamp O, Lang F, Guibins E. Fas- or ceramide-induced apoptosis is mediated by a Rac1-regulated activation of Jun N-terminal kinase/p38 kinases and GADD153. J Biol Chem. 272:1997;22173-22181.
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Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons
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of special interest. Active forms of both PI3K and Akt/PKB are able to protect superior cervial neurons from NGF withdrawal. However, inhibition of the PI3K/Akt pathway by pharmacological inhibitors or dominant-negative PI3K do not induce apoptosis. Hence, NGF activates several independent survival pathways, one of them being that activated via PI3K/Akt.
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of special interest Philpott KL, McCarthy MJ, Klippel A, Rubin LL. Activated phosphatidylinositol 3-kinase and Akt kinase promote survival of superior cervical neurons. J Cell Biol. 139:1997;809-815 Active forms of both PI3K and Akt/PKB are able to protect superior cervial neurons from NGF withdrawal. However, inhibition of the PI3K/Akt pathway by pharmacological inhibitors or dominant-negative PI3K do not induce apoptosis. Hence, NGF activates several independent survival pathways, one of them being that activated via PI3K/Akt.
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J Cell Biol
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Philpott, K.L.1
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Klippel, A.3
Rubin, L.L.4
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Phosphatidylinositol 3-kinase and akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons
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Crowder RJ, Freeman RS. Phosphatidylinositol 3-kinase and akt protein kinase are necessary and sufficient for the survival of nerve growth factor-dependent sympathetic neurons. J Neurosci. 18:1998;2933-2943.
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Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway
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Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery
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of outstanding interest. This work demonstrates that BAD is a substrate for Akt, in vitro as well as in vivo, and identifies Ser136 of BAD as the residue phosphorylated by Akt. Importantly, this study shows that BAD phosphorylation by Akt is sufficient to inhibit BAD pro-apoptotic function in vivo.
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of outstanding interest Data SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 91:1997;231-241 This work demonstrates that BAD is a substrate for Akt, in vitro as well as in vivo, and identifies Ser136 of BAD as the residue phosphorylated by Akt. Importantly, this study shows that BAD phosphorylation by Akt is sufficient to inhibit BAD pro-apoptotic function in vivo.
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Data, S.R.1
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Greenberg, M.E.7
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44
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1842333237
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Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt
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of outstanding interest. This study identifies the signalling pathway triggered by IL-3 stimulation that results in BAD phosphorylation. IL-3 induced BAD phosphorylation and Akt activation are blocked by PI3K inhibitions in a dose-dependent manner. In addition, Akt is able to induce BAD phosphorylation in vivo and in vitro at the same serine residues phosphorylated in vivo in response to IL-3.
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of outstanding interest del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science. 278:1997;687-689 This study identifies the signalling pathway triggered by IL-3 stimulation that results in BAD phosphorylation. IL-3 induced BAD phosphorylation and Akt activation are blocked by PI3K inhibitions in a dose-dependent manner. In addition, Akt is able to induce BAD phosphorylation in vivo and in vitro at the same serine residues phosphorylated in vivo in response to IL-3.
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Science
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Del Peso, L.1
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Parry RV, Reif K, Smith G, Sansom DM, Hemmings BA, Ward SG. Ligation of the T cell co-stimulatory receptor CD28 activates the serine-threonine protein kinase protein kinase B. Eur J Immunol. 27:1997;2495-2501.
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Ward, S.G.6
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47
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Genetic analysis of protein kinase B (AKT) in Drosophila
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of outstanding interest. This study shows that in Drosophila, Akt/PKB regulates cell death. The relevance of this work is that it corroborates that Akt is required for survival in an animal model.
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of outstanding interest Staveley BE, Ruel L, Jin J, Stambolic V, Mastronardi FG, Heitzler P, Woodgett JR, Manoukian AS. Genetic analysis of protein kinase B (AKT) in Drosophila. Curr Biol. 8:1998;599-602 This study shows that in Drosophila, Akt/PKB regulates cell death. The relevance of this work is that it corroborates that Akt is required for survival in an animal model.
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49
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50
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51
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Bcl-2 phosphorylation required for anti-apoptotic function
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of special interest. This is one of the best studies about Bcl-2 phosphorylation. It identifies Ser70 as the Bcl-2 residue phosphorylated in vivo in response to extracellular signals. Interestingly, mutation of Ser70 to alanine prevents the protective function of Bcl-2 against IL-3 withdraw and etoposide-induced apoptosis. Consistent with this finding, mutation of Ser70 to glutamic acid, which mimics phosphorylation, enhances Bcl-2's anti-apoptotic function.
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of special interest Ito T, Deng X, Carr B, May WS. Bcl-2 phosphorylation required for anti-apoptotic function. J Biol Chem. 272:1997;11671-11673 This is one of the best studies about Bcl-2 phosphorylation. It identifies Ser70 as the Bcl-2 residue phosphorylated in vivo in response to extracellular signals. Interestingly, mutation of Ser70 to alanine prevents the protective function of Bcl-2 against IL-3 withdraw and etoposide-induced apoptosis. Consistent with this finding, mutation of Ser70 to glutamic acid, which mimics phosphorylation, enhances Bcl-2's anti-apoptotic function.
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55
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The activation of p38 and apoptosis by the inhibition of erk is antagonized by the phosphoinositide 3-kinase/Akt pathway
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Berra E, Diaz-Meco J, Moscat J. The activation of p38 and apoptosis by the inhibition of erk is antagonized by the phosphoinositide 3-kinase/Akt pathway. J Biol Chem. 273:1998;10792-10797.
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58
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Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B
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of outstanding interest. CD95/Fas-induced apoptosis is enhanced by inhibition of PI3K. Active forms of both PI3K and Akt/PKB are able to protect from overexpression of CD95. Interestingly, PI3K and Akt/PKB also protect from FADD, an adaptor molecule that links the CD95 surface receptor with caspase 8. These results suggest that Akt/PKB might block apoptosis at the level of caspase activation.
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of outstanding interest Hausler P, Papoff G, Eramo A, Reif K, Cantrell DA, Ruberti G. Protection of CD95-mediated apoptosis by activation of phosphatidylinositide 3-kinase and protein kinase B. Eur J Immunol. 28:1998;57-69 CD95/Fas-induced apoptosis is enhanced by inhibition of PI3K. Active forms of both PI3K and Akt/PKB are able to protect from overexpression of CD95. Interestingly, PI3K and Akt/PKB also protect from FADD, an adaptor molecule that links the CD95 surface receptor with caspase 8. These results suggest that Akt/PKB might block apoptosis at the level of caspase activation.
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Papoff, G.2
Eramo, A.3
Reif, K.4
Cantrell, D.A.5
Ruberti, G.6
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