| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
J Biol Chem, Vol. 273, Issue 26, 16568-16575, June 26, 1998
From the Ceramide is an important lipid messenger involved
in mediating a variety of cell functions including apoptosis. However,
mechanisms responsible for ceramide-induced apoptosis remain unclear.
We investigated the possibility that ceramide may decrease
antiapoptotic signaling in cells by inhibiting Akt kinase activity. Our
data show that C2-ceramide induces apoptosis in HMN1
motor neuron cells and decreases both basal and insulin- or
serum-stimulated Akt kinase activity 65-70%. These results are
consistent with decreased Akt kinase activity being involved in the
apoptotic effects of ceramide. This possibility is further supported by
studies showing that constitutively active Akt kinase decreases
C2-ceramide-induced death of HMN1 cells as well as COS-7
cells. Decreased Akt activity is not due to ceramide activating the
ceramide-activated protein phosphatase or to a direct inhibition of Akt
kinase by ceramide, suggesting that ceramide acts upstream of Akt
kinase to decrease its activity. Treating cells with
C2-ceramide does not affect phosphorylation of insulin
receptor substrate-1, interactions between insulin receptor substrate-1
and p85, or insulin-stimulated phosphatidylinositol 3-kinase activity,
suggesting that the effects of C2-ceramide on Akt kinase
are not mediated through modulating phosphatidylinositol 3-kinase. In
sum, our results suggest that inhibition of the key antiapoptotic
kinase, Akt, may play an important role in ceramide-induced
apoptosis.
Inhibition of Akt Kinase by Cell-permeable Ceramide and Its
Implications for Ceramide-induced Apoptosis
,
Department of Pharmacology,
§ Howard Hughes Medical Institute, and Department of
Medicine, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania 19104
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  J. Jin, Q. Hou, T. D. Mullen, Y. H. Zeidan, J. Bielawski, J. M. Kraveka, A. Bielawska, L. M. Obeid, Y. A. Hannun, and Y.-T. Hsu Ceramide Generated by Sphingomyelin Hydrolysis and the Salvage Pathway Is Involved in Hypoxia/Reoxygenation-induced Bax Redistribution to Mitochondria in NT-2 Cells J. Biol. Chem., September 26, 2008; 283(39): 26509 - 26517. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Anderson and J. Borlak Molecular Mechanisms and Therapeutic Targets in Steatosis and Steatohepatitis Pharmacol. Rev., September 1, 2008; 60(3): 311 - 357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Tran, C. D. Smith, M. Kester, and G. P. Robertson Combining Nanoliposomal Ceramide with Sorafenib Synergistically Inhibits Melanoma and Breast Cancer Cell Survival to Decrease Tumor Development Clin. Cancer Res., June 1, 2008; 14(11): 3571 - 3581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. Poitout and R. P. Robertson Glucolipotoxicity: Fuel Excess and {beta}-Cell Dysfunction Endocr. Rev., May 1, 2008; 29(3): 351 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Pickersgill, G. J. Litherland, A. S. Greenberg, M. Walker, and S. J. Yeaman Key Role for Ceramides in Mediating Insulin Resistance in Human Muscle Cells J. Biol. Chem., April 27, 2007; 282(17): 12583 - 12589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Kitatani, J. Idkowiak-Baldys, J. Bielawski, T. A. Taha, R. W. Jenkins, C. E. Senkal, B. Ogretmen, L. M. Obeid, and Y. A. Hannun Protein Kinase C-induced Activation of a Ceramide/Protein Phosphatase 1 Pathway Leading to Dephosphorylation of p38 MAPK J. Biol. Chem., December 1, 2006; 281(48): 36793 - 36802. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V E MacRae, T Burdon, S F Ahmed, and C Farquharson Ceramide inhibition of chondrocyte proliferation and bone growth is IGF-I independent. J. Endocrinol., November 1, 2006; 191(2): 369 - 377. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. E. MacRae, C. Farquharson, and S. F. Ahmed The pathophysiology of the growth plate in juvenile idiopathic arthritis Rheumatology, January 1, 2006; 45(1): 11 - 19. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-F. Lin, C.-L. Chen, W.-T. Chang, M.-S. Jan, L.-J. Hsu, R.-H. Wu, Y.-T. Fang, M.-J. Tang, W.-C. Chang, and Y.-S. Lin Bcl-2 Rescues Ceramide- and Etoposide-induced Mitochondrial Apoptosis through Blockage of Caspase-2 Activation J. Biol. Chem., June 24, 2005; 280(25): 23758 - 23765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Stover, A. Sharma, G. P. Robertson, and M. Kester Systemic Delivery of Liposomal Short-Chain Ceramide Limits Solid Tumor Growth in Murine Models of Breast Adenocarcinoma Clin. Cancer Res., May 1, 2005; 11(9): 3465 - 3474. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Papadia, P. Stevenson, N. R. Hardingham, H. Bading, and G. E. Hardingham Nuclear Ca2+ and the cAMP Response Element-Binding Protein Family Mediate a Late Phase of Activity-Dependent Neuroprotection J. Neurosci., April 27, 2005; 25(17): 4279 - 4287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Salim, R. P. Nacamuli, E. F. Morgan, A. J. Giaccia, and M. T. Longaker Transient Changes in Oxygen Tension Inhibit Osteogenic Differentiation and Runx2 Expression in Osteoblasts J. Biol. Chem., September 17, 2004; 279(38): 40007 - 40016. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Stratford, K. L. Hoehn, F. Liu, and S. A. Summers Regulation of Insulin Action by Ceramide: DUAL MECHANISMS LINKING CERAMIDE ACCUMULATION TO THE INHIBITION OF Akt/PROTEIN KINASE B J. Biol. Chem., August 27, 2004; 279(35): 36608 - 36615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Weyrich, K. Kapp, G. Niederfellner, M. Melzer, R. Lehmann, H.-U. Haring, and R. Lammers Partitioning-Defective Protein 6 Regulates Insulin-Dependent Glycogen Synthesis via Atypical Protein Kinase C Mol. Endocrinol., May 1, 2004; 18(5): 1287 - 1300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Scarlatti, C. Bauvy, A. Ventruti, G. Sala, F. Cluzeaud, A. Vandewalle, R. Ghidoni, and P. Codogno Ceramide-mediated Macroautophagy Involves Inhibition of Protein Kinase B and Up-regulation of Beclin 1 J. Biol. Chem., April 30, 2004; 279(18): 18384 - 18391. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Rodriguez-Iturbe, N. D. Vaziri, J. Herrera-Acosta, and R. J. Johnson Oxidative stress, renal infiltration of immune cells, and salt-sensitive hypertension: all for one and one for all Am J Physiol Renal Physiol, April 1, 2004; 286(4): F606 - F616. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Adams II, T. Pratipanawatr, R. Berria, E. Wang, R. A. DeFronzo, M. C. Sullards, and L. J. Mandarino Ceramide Content Is Increased in Skeletal Muscle From Obese Insulin-Resistant Humans Diabetes, January 1, 2004; 53(1): 25 - 31. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Powell, E. Hajduch, G. Kular, and H. S. Hundal Ceramide Disables 3-Phosphoinositide Binding to the Pleckstrin Homology Domain of Protein Kinase B (PKB)/Akt by a PKC{zeta}-Dependent Mechanism Mol. Cell. Biol., November 1, 2003; 23(21): 7794 - 7808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Stover and M. Kester Liposomal Delivery Enhances Short-Chain Ceramide-Induced Apoptosis of Breast Cancer Cells J. Pharmacol. Exp. Ther., November 1, 2003; 307(2): 468 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Hundal, A. Gomez-Munoz, J. Y. Kong, B. S. Salh, A. Marotta, V. Duronio, and U. P. Steinbrecher Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels J. Biol. Chem., June 27, 2003; 278(27): 24399 - 24408. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Jambal, S. Masterson, A. Nesterova, R. Bouchard, B. Bergman, J. C. Hutton, L. M. Boxer, J. E.-B. Reusch, and S. Pugazhenthi Cytokine-mediated Down-regulation of the Transcription Factor cAMP-response Element-binding Protein in Pancreatic {beta}-Cells J. Biol. Chem., June 13, 2003; 278(25): 23055 - 23065. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Koide, T. Sugiyama, I. Mori, M. M. Mu, T. Yoshida, and T. Yokochi C 2-ceramide inhibits LPS-induced nitric oxide production in RAW 264.7 macrophage cells through down-regulating the activation of Akt Innate Immunity, April 1, 2003; 9(2): 85 - 90. [Abstract] [PDF]
|
|
|
|
|
|
J. A. Chavez, T. A. Knotts, L.-P. Wang, G. Li, R. T. Dobrowsky, G. L. Florant, and S. A. Summers A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids J. Biol. Chem., March 14, 2003; 278(12): 10297 - 10303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Auge, V. Garcia, F. Maupas-Schwalm, T. Levade, R. Salvayre, and A. Negre-Salvayre Oxidized LDL-Induced Smooth Muscle Cell Proliferation Involves the EGF Receptor/PI-3 Kinase/Akt and the Sphingolipid Signaling Pathways Arterioscler. Thromb. Vasc. Biol., December 1, 2002; 22(12): 1990 - 1995. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. K. Pru, I. R. Hendry, J. S. Davis, and B. R. Rueda Soluble Fas Ligand Activates the Sphingomyelin Pathway and Induces Apoptosis in Luteal Steroidogenic Cells Independently of Stress-Activated p38MAPK Endocrinology, November 1, 2002; 143(11): 4350 - 4357. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Martin, M. Salinas, N. Fujita, T. Tsuruo, and A. Cuadrado Ceramide and Reactive Oxygen Species Generated by H2O2 Induce Caspase-3-independent Degradation of Akt/Protein Kinase B J. Biol. Chem., November 1, 2002; 277(45): 42943 - 42952. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. O. Karpinich, M. Tafani, R. J. Rothman, M. A. Russo, and J. L. Farber The Course of Etoposide-induced Apoptosis from Damage to DNA and p53 Activation to Mitochondrial Release of Cytochrome c J. Biol. Chem., May 3, 2002; 277(19): 16547 - 16552. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Vieu, F. Terce, F. Chevy, C. Rolland, R. Barbaras, H. Chap, C. Wolf, B. Perret, and X. Collet Coupled assay of sphingomyelin and ceramide molecular species by gas liquid chromatography J. Lipid Res., March 1, 2002; 43(3): 510 - 522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Bourbon, L. Sandirasegarane, and M. Kester Ceramide-induced Inhibition of Akt Is Mediated through Protein Kinase Czeta . IMPLICATIONS FOR GROWTH ARREST J. Biol. Chem., January 25, 2002; 277(5): 3286 - 3292. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. Zhang, D. F. Spandau, and A. Roman E5 Protein of Human Papillomavirus Type 16 Protects Human Foreskin Keratinocytes from UV B-Irradiation-Induced Apoptosis J. Virol., January 1, 2002; 76(1): 220 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Qi, P. Juo, J. Masuda-Robens, M. J. Caloca, H. Zhou, N. Stone, M. G. Kazanietz, and M. M. Chou Caspase-mediated Cleavage of the TIAM1 Guanine Nucleotide Exchange Factor during Apoptosis Cell Growth Differ., December 1, 2001; 12(12): 603 - 611. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Yan, S. K. John, and D. B. Polk Kinase Suppressor of Ras Determines Survival of Intestinal Epithelial Cells Exposed to Tumor Necrosis Factor Cancer Res., December 1, 2001; 61(24): 8668 - 8675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Tenzer, D. Zingg, S. Rocha, B. Hemmings, D. Fabbro, C. Glanzmann, P. A. Schubiger, S. Bodis, and M. Pruschy The Phosphatidylinositide 3'-Kinase/Akt Survival Pathway Is a Target for the Anticancer and Radiosensitizing Agent PKC412, an Inhibitor of Protein Kinase C Cancer Res., November 1, 2001; 61(22): 8203 - 8210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Teruel, R. Hernandez, and M. Lorenzo Ceramide Mediates Insulin Resistance by Tumor Necrosis Factor-{alpha} in Brown Adipocytes by Maintaining Akt in an Inactive Dephosphorylated State Diabetes, November 1, 2001; 50(11): 2563 - 2571. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Cuvillier and T. Levade Sphingosine 1-phosphate antagonizes apoptosis of human leukemia cells by inhibiting release of cytochrome c and Smac/DIABLO from mitochondria Blood, November 1, 2001; 98(9): 2828 - 2836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Cazzolli, L. Carpenter, T. J. Biden, and C. Schmitz-Peiffer A Role for Protein Phosphatase 2A-Like Activity, but Not Atypical Protein Kinase C{zeta}, in the Inhibition of Protein Kinase B/Akt and Glycogen Synthesis by Palmitate Diabetes, October 1, 2001; 50(10): 2210 - 2218. [Abstract] [Full Text]
|
|
|
|
 |
|
 T. Kanto, P. Kalinski, O. C. Hunter, M. T. Lotze, and A. A. Amoscato2 Ceramide Mediates Tumor-Induced Dendritic Cell Apoptosis J. Immunol., October 1, 2001; 167(7): 3773 - 3784. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Laurent and J.-P. Jaffrezou Signaling pathways activated by daunorubicin Blood, August 15, 2001; 98(4): 913 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Maurer, L. Melton, C. Billups, M. C. Cabot, and C. P. Reynolds Synergistic Cytotoxicity in Solid Tumor Cell Lines Between N-(4-Hydroxyphenyl)retinamide and Modulators of Ceramide Metabolism J Natl Cancer Inst, December 6, 2000; 92(23): 1897 - 1909. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. C. Sparagna, D. L. Hickson-Bick, L. M. Buja, and J. B. McMillin A metabolic role for mitochondria in palmitate-induced cardiac myocyte apoptosis Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2124 - H2132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Zhou, X.-M. Li, J. Meinkoth, and R. N. Pittman Akt Regulates Cell Survival and Apoptosis at a Postmitochondrial Level J. Cell Biol., October 23, 2000; 151(3): 483 - 494. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Ramljak, R. J. Calvert, P. W. Wiesenfeld, B. A. Diwan, B. Catipovic, W. F.O. Marasas, T. C. Victor, L. M. Anderson, and W. C.A. Gelderblom A potential mechanism for fumonisin B1-mediated hepatocarcinogenesis: cyclin D1 stabilization associated with activation of Akt and inhibition of GSK-3{beta} activity Carcinogenesis, August 1, 2000; 21(8): 1537 - 1546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. Green Apoptosis and Sphingomyelin Hydrolysis: The Flip Side J. Cell Biol., July 11, 2000; 150(1): F5 - F8. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Wang, K. D. McCullough, T. F. Franke, and N. J. Holbrook Epidermal Growth Factor Receptor-dependent Akt Activation by Oxidative Stress Enhances Cell Survival J. Biol. Chem., May 5, 2000; 275(19): 14624 - 14631. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Schubert, M. P. Scheid, and V. Duronio Ceramide Inhibits Protein Kinase B/Akt by Promoting Dephosphorylation of Serine 473 J. Biol. Chem., April 28, 2000; 275(18): 13330 - 13335. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Tang, H. Zhou, A. Chen, R. N. Pittman, and J. Field The Akt Proto-oncogene Links Ras to Pak and Cell Survival Signals J. Biol. Chem., March 24, 2000; 275(13): 9106 - 9109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Burow, C. B. Weldon, B. M. Collins-Burow, N. Ramsey, A. McKee, A. Klippel, J. A. McLachlan, S. Clejan, and B. S. Beckman Cross-talk between Phosphatidylinositol 3-Kinase and Sphingomyelinase Pathways as a Mechanism for Cell Survival/Death Decisions J. Biol. Chem., March 24, 2000; 275(13): 9628 - 9635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Kondo, T. Matsuda, M. Tashima, H. Umehara, N. Domae, K. Yokoyama, T. Uchiyama, and T. Okazaki Suppression of Heat Shock Protein-70 by Ceramide in Heat Shock-induced HL-60 Cell Apoptosis J. Biol. Chem., March 17, 2000; 275(12): 8872 - 8879. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Zundel, L. M. Swiersz, and A. Giaccia Caveolin 1-Mediated Regulation of Receptor Tyrosine Kinase-Associated Phosphatidylinositol 3-Kinase Activity by Ceramide Mol. Cell. Biol., March 1, 2000; 20(5): 1507 - 1514. [Abstract] [Full Text]
|
|
|
|
|
|
A. Erdreich-Epstein, H. Shimada, S. Groshen, M. Liu, L. S. Metelitsa, K. S. Kim, M. F. Stins, R. C. Seeger, and D. L. Durden Integrins {{alpha}}v{beta}3 and {{alpha}}v{beta}5 Are Expressed by Endothelium of High-Risk Neuroblastoma and Their Inhibition Is Associated with Increased Endogenous Ceramide Cancer Res., February 1, 2000; 60(3): 712 - 721. [Abstract] [Full Text]
|
|
|
|
 |
|
 S. R. Datta, A. Brunet, and M. E. Greenberg Cellular survival: a play in three Akts Genes & Dev., November 15, 1999; 13(22): 2905 - 2927. [Full Text]
|
|
|
|
 |
|
 S.A. Cook and P.A. Poole-Wilson Cardiac myocyte apoptosis Eur. Heart J., November 2, 1999; 20(22): 1619 - 1629. [PDF]
|
|
|
|
|
|
C. Schmitz-Peiffer, D. L. Craig, and T. J. Biden Ceramide Generation Is Sufficient to Account for the Inhibition of the Insulin-stimulated PKB Pathway in C2C12 Skeletal Muscle Cells Pretreated with Palmitate J. Biol. Chem., August 20, 1999; 274(34): 24202 - 24210. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Scaffidi, I. Schmitz, J. Zha, S. J. Korsmeyer, P. H. Krammer, and M. E. Peter Differential Modulation of Apoptosis Sensitivity in CD95 Type I and Type II Cells J. Biol. Chem., August 6, 1999; 274(32): 22532 - 22538. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P. Ruvolo, X. Deng, T. Ito, B. K. Carr, and W. S. May Ceramide Induces Bcl2 Dephosphorylation via a Mechanism Involving Mitochondrial PP2A J. Biol. Chem., July 16, 1999; 274(29): 20296 - 20300. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. C. Weihl, G. D. Ghadge, S. G. Kennedy, N. Hay, R. J. Miller, and R. P. Roos Mutant Presenilin-1 Induces Apoptosis and Downregulates Akt/PKB J. Neurosci., July 1, 1999; 19(13): 5360 - 5369. [Abstract] [Full Text] [PDF]
|
|
< |
