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Science 13 November 1998:
Vol. 282. no. 5392, pp. 1318 - 1321
DOI: 10.1126/science.282.5392.1318
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Reports

Regulation of Cell Death Protease Caspase-9 by Phosphorylation

Michael H. Cardone, *dagger Natalie Roy, * Henning R. Stennicke, Guy S. Salvesen, Thomas F. Franke, Eric Stanbridge, Steven Frisch, John C. Reed ddagger

Caspases are intracellular proteases that function as initiators and effectors of apoptosis. The kinase Akt and p21-Ras, an Akt activator, induced phosphorylation of pro-caspase-9 (pro-Casp9) in cells. Cytochrome c-induced proteolytic processing of pro-Casp9 was defective in cytosolic extracts from cells expressing either active Ras or Akt. Akt phosphorylated recombinant Casp9 in vitro on serine-196 and inhibited its protease activity. Mutant pro-Casp9(Ser196Ala) was resistant to Akt-mediated phosphorylation and inhibition in vitro and in cells, resulting in Akt-resistant induction of apoptosis. Thus, caspases can be directly regulated by protein phosphorylation.

M. H. Cardone, Program on Apoptosis and Cell Death Research, The Burnham Institute, La Jolla, CA 92037, USA, and Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. N. Roy, H. R. Stennicke, G. S. Salvesen, S. Frisch, J. C. Reed, Program on Apoptosis and Cell Death Research, The Burnham Institute, La Jolla, CA 92037, USA. T. F. Franke, Department of Pharmacology, Columbia University, New York, NY 10032, USA. E. Stanbridge, Department of Microbiology and Molecular Genetics, University of California at Irvine, Irvine, CA 92697-4025, USA.
*   These authors contributed equally to this work.

dagger    Present address: Department of Biology, MIT, Cambridge, MA 02139, USA.

ddagger    To whom correspondence should be addressed at The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA. E-mail: jreed{at}burnham-inst.org.

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A Peptide Conjugate of Vitamin E Succinate Targets Breast Cancer Cells with High ErbB2 Expression.
X.-F. Wang, M. Birringer, L.-F. Dong, P. Veprek, P. Low, E. Swettenham, M. Stantic, L.-H. Yuan, R. Zobalova, K. Wu, et al. (2007)
Cancer Res. 67, 3337-3344
   Abstract »    Full Text »    PDF »
Influenza A Virus NS1 Protein Activates the PI3K/Akt Pathway To Mediate Antiapoptotic Signaling Responses.
C. Ehrhardt, T. Wolff, S. Pleschka, O. Planz, W. Beermann, J. G. Bode, M. Schmolke, and S. Ludwig (2007)
J. Virol. 81, 3058-3067
   Abstract »    Full Text »    PDF »
Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines.
W.-T. Choi, M. Kaul, S. Kumar, J. Wang, I. M. K. Kumar, C.-Z. Dong, J. An, S. A. Lipton, and Z. Huang (2007)
J. Biol. Chem. 282, 7154-7163
   Abstract »    Full Text »    PDF »
Endoplasmic reticulum stress exacerbates ischemia-reperfusion-induced apoptosis through attenuation of Akt protein synthesis in human choriocarcinoma cells.
H.-w. Yung, S. Korolchuk, A. M. Tolkovsky, D. S. Charnock-Jones, and G. J. Burton (2007)
FASEB J 21, 872-884
   Abstract »    Full Text »    PDF »
Substance P mediates antiapoptotic responses in human colonocytes by Akt activation.
H.-W. Koon, D. Zhao, Y. Zhan, M. P. Moyer, and C. Pothoulakis (2007)
PNAS 104, 2013-2018
   Abstract »    Full Text »    PDF »
Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis.
J. L. Arbiser, T. Kau, M. Konar, K. Narra, R. Ramchandran, S. A. Summers, C. J. Vlahos, K. Ye, B. N. Perry, W. Matter, et al. (2007)
Blood 109, 560-565
   Abstract »    Full Text »    PDF »
Evidence for Two Modes of Development of Acquired Tumor Necrosis Factor-related Apoptosis-inducing Ligand Resistance: INVOLVEMENT OF Bcl-xL.
J. J. Song, J. Y. An, Y. T. Kwon, and Y. J. Lee (2007)
J. Biol. Chem. 282, 319-328
   Abstract »    Full Text »    PDF »
Mitochondrial Membrane Permeabilization in Cell Death.
G. Kroemer, L. Galluzzi, and C. Brenner (2007)
Physiol Rev 87, 99-163
   Abstract »    Full Text »    PDF »
Intracellular and extracellular functions of heat shock proteins: repercussions in cancer therapy.
E. Schmitt, M. Gehrmann, M. Brunet, G. Multhoff, and C. Garrido (2007)
J. Leukoc. Biol. 81, 15-27
   Abstract »    Full Text »    PDF »
Cyclic GMP-dependent Protein Kinase I{alpha} Attenuates Necrosis and Apoptosis Following Ischemia/Reoxygenation in Adult Cardiomyocyte.
A. Das, A. Smolenski, S. M. Lohmann, and R. C. Kukreja (2006)
J. Biol. Chem. 281, 38644-38652
   Abstract »    Full Text »    PDF »
MDM2 Is Required for Suppression of Apoptosis by Activated Akt1 in Salivary Acinar Cells.
K. H. Limesand, K. L. Schwertfeger, and S. M. Anderson (2006)
Mol. Cell. Biol. 26, 8840-8856
   Abstract »    Full Text »    PDF »
Coadministration of Sorafenib with Rottlerin Potently Inhibits Cell Proliferation and Migration in Human Malignant Glioma Cells.
E. P. Jane, D. R. Premkumar, and I. F. Pollack (2006)
J. Pharmacol. Exp. Ther. 319, 1070-1080
   Abstract »    Full Text »    PDF »
Ouabain induces cell proliferation through calcium-dependent phosphorylation of Akt (protein kinase B) in opossum kidney proximal tubule cells.
S. J. Khundmiri, M. A. Metzler, M. Ameen, V. Amin, M. J. Rane, and N. A. Delamere (2006)
Am J Physiol Cell Physiol 291, C1247-C1257
   Abstract »    Full Text »    PDF »
Chronic Protein Kinase B (PKB/c-akt) Activation Leads to Apoptosis Induced by Oxidative Stress-Mediated Foxo3a Transcriptional Up-regulation..
A. G.M. van Gorp, K. M. Pomeranz, K. U. Birkenkamp, R. C-Y. Hui, E. W-F. Lam, and P. J. Coffer (2006)
Cancer Res. 66, 10760-10769
   Abstract »    Full Text »    PDF »
Fas-Mediated Apoptosis in Cholangiocarcinoma Cells Is Enhanced by 3,3'-Diindolylmethane through Inhibition of AKT Signaling and FLICE-Like Inhibitory Protein.
Y. Chen, J. Xu, N. Jhala, P. Pawar, Z. B. Zhu, L. Ma, C.-H. Byon, and J. M. McDonald (2006)
Am. J. Pathol. 169, 1833-1842
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PYK2 mediates anti-apoptotic AKT signaling in response to benzo[a]pyrene diol epoxide in mammary epithelial cells.
A. D. Burdick, I. D. Ivnitski-Steele, F. T. Lauer, and S. W. Burchiel (2006)
Carcinogenesis 27, 2331-2340
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Quercetin Induces Apoptosis via Caspase Activation, Regulation of Bcl-2, and Inhibition of PI-3-Kinase/Akt and ERK Pathways in a Human Hepatoma Cell Line (HepG2).
A. B. Granado-Serrano, M. A. Martin, L. Bravo, L. Goya, and S. Ramos (2006)
J. Nutr. 136, 2715-2721
   Abstract »    Full Text »    PDF »
Rapid nongenomic actions of thyroid hormone.
Y. Hiroi, H.-H. Kim, H. Ying, F. Furuya, Z. Huang, T. Simoncini, K. Noma, K. Ueki, N.-H. Nguyen, T. S. Scanlan, et al. (2006)
PNAS 103, 14104-14109
   Abstract »    Full Text »    PDF »
Overexpression of HAX-1 Protects Cardiac Myocytes From Apoptosis Through Caspase-9 Inhibition.
Y. Han, Y.-S. Chen, Z. Liu, N. Bodyak, D. Rigor, E. Bisping, W. T. Pu, and P. M. Kang (2006)
Circ. Res. 99, 415-423
   Abstract »    Full Text »    PDF »
TRAIL-Mediated Apoptosis in HIV-1-Infected Macrophages Is Dependent on the Inhibition of Akt-1 Phosphorylation.
Y. Huang, N. Erdmann, H. Peng, S. Herek, J. S. Davis, X. Luo, T. Ikezu, and J. Zheng (2006)
J. Immunol. 177, 2304-2313
   Abstract »    Full Text »    PDF »


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