Home LiteratureArticle Details
PMID: 15899875 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

FLIP protects against hypoxia/reoxygenation-induced endothelial cell apoptosis by inhibiting Bax activation.

Molecular and cellular biology ·Vol. 25 ·No. 11 ·2005-06-00 ·Pages 4742-51

Wang X, Wang Y, Zhang J, Kim HP, Ryter SW, Choi AM

Abstract

Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid(-/-) MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (alpha, zeta) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-X(L), an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.

MeSH Terms
Animals Apoptosis BH3 Interacting Domain Death Agonist Protein CASP8 and FADD-Like Apoptosis Regulating Protein Carrier Proteins/antagonists & inhibitors,metabolism Caspase 8 Caspase Inhibitors Caspases/metabolism Cell Hypoxia Cell Membrane/metabolism Death Domain Receptor Signaling Adaptor Proteins Endothelial Cells/metabolism Humans Intracellular Signaling Peptides and Proteins/genetics,metabolism Lung/cytology Mice Protein Kinase C/metabolism Protein Transport Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors,metabolism Receptors, Tumor Necrosis Factor/metabolism bcl-2-Associated X Protein
Chemicals
BAX protein, human BH3 Interacting Domain Death Agonist Protein BID protein, human Bax protein, mouse Bid protein, mouse CASP8 and FADD-Like Apoptosis Regulating Protein CFLAR protein, human Carrier Proteins Caspase Inhibitors Cflar protein, mouse Death Domain Receptor Signaling Adaptor Proteins Intracellular Signaling Peptides and Proteins Proto-Oncogene Proteins c-bcl-2 Receptors, Tumor Necrosis Factor bcl-2-Associated X Protein Protein Kinase C CASP8 protein, human Casp8 protein, mouse Caspase 8 Caspases
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Wang Xue
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, 3459 Fifth Ave., MUH NW 628, Pittsburgh, PA 15213, USA.
Wang Yong
Zhang Jinglan
Kim Hong Pyo
Ryter Stefan W
Choi Augustine M K
References (44)
44 references, click to expand
  1. Inhibition of mitogen-activated kinase signaling sensitizes HeLa cells to Fas receptor-mediated apoptosis.
    Mol Cell Biol. 1999 Sep;19(9):5991-6002 PMID: 10454546
  2. PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits.
    Am J Physiol. 1999 May;276(5 Pt 2):H1468-81 PMID: 10330229
  3. Selective up-regulation of phosphatidylinositol 3'-kinase activity in Th2 cells inhibits caspase-8 cleavage at the death-inducing complex: a mechanism for Th2 resistance from Fas-mediated apoptosis.
    J Immunol. 1999 Nov 1;163(9):4772-9 PMID: 10528176
  4. Bcl-XL disrupts death-inducing signal complex formation in plasma membrane induced by hypoxia/reoxygenation.
    FASEB J. 2004 Dec;18(15):1826-33 PMID: 15576486
  5. The differential expression of apoptosis factors in the alveolar epithelium is redox sensitive and requires NF-kappaB (RelA)-selective targeting.
    Biochem Biophys Res Commun. 2000 Apr 29;271(1):257-67 PMID: 10777712
  6. The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways.
    Curr Biol. 2000 Jun 1;10(11):640-8 PMID: 10837247
  7. Involvement of CD95/Apo1/Fas in cell death after myocardial ischemia.
    Circulation. 2000 Aug 22;102(8):915-20 PMID: 10952962
  8. MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly.
    EMBO J. 2000 Oct 16;19(20):5418-28 PMID: 11032809
  9. Signal pathway involved in the development of hypoxic preconditioning in rat hepatocytes.
    Hepatology. 2001 Jan;33(1):131-9 PMID: 11124829
  10. Protein kinase C-theta mediates a selective T cell survival signal via phosphorylation of BAD.
    J Immunol. 2001 May 15;166(10):5955-63 PMID: 11342610
  11. Cellular FLICE-inhibitory protein splice variants inhibit different steps of caspase-8 activation at the CD95 death-inducing signaling complex.
    J Biol Chem. 2001 Jun 8;276(23):20633-40 PMID: 11279218
  12. Protein kinase C regulates FADD recruitment and death-inducing signaling complex formation in Fas/CD95-induced apoptosis.
    J Biol Chem. 2001 Nov 30;276(48):44944-52 PMID: 11581255
  13. Direct targeting of cis-Golgi matrix proteins to the Golgi apparatus.
    J Cell Sci. 2001 Nov;114(Pt 22):4105-15 PMID: 11739642
  14. BID mediates neuronal cell death after oxygen/ glucose deprivation and focal cerebral ischemia.
    Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15318-23 PMID: 11742085
  15. Death effector domain-only polypeptides of caspase-8 and -10 specifically inhibit death receptor-induced cell death.
    Biochem Biophys Res Commun. 2002 Mar 1;291(3):484-93 PMID: 11855814
  16. The Apaf-1 apoptosome: a large caspase-activating complex.
    Biochimie. 2002 Feb-Mar;84(2-3):203-14 PMID: 12022951
  17. Protein kinase C isoforms and lipid second messengers: a critical nuclear partnership?
    Histol Histopathol. 2002 Oct;17(4):1311-6 PMID: 12371155
  18. Bid-mediated mitochondrial pathway is critical to ischemic neuronal apoptosis and focal cerebral ischemia.
    J Biol Chem. 2002 Nov 1;277(44):42074-81 PMID: 12200426
  19. Regulation of cell cycle progression and apoptosis by the Ras/Raf/MEK/ERK pathway (Review).
    Int J Oncol. 2003 Mar;22(3):469-80 PMID: 12579299
  20. FAP-1 association with Fas (Apo-1) inhibits Fas expression on the cell surface.
    Mol Cell Biol. 2003 May;23(10):3623-35 PMID: 12724420
  21. Cholesterol distribution in the Golgi complex of DITNC1 astrocytes is differentially altered by fresh and aged amyloid beta-peptide-(1-42).
    J Biol Chem. 2003 May 9;278(19):17150-7 PMID: 12584199
  22. Cellular FLICE-inhibitory protein: an attractive therapeutic target?
    Expert Opin Ther Targets. 2003 Aug;7(4):559-73 PMID: 12885274
  23. Protein kinase Cepsilon interacts with Bax and promotes survival of human prostate cancer cells.
    Oncogene. 2003 Sep 11;22(39):7958-68 PMID: 12970744
  24. The death effector domain protein family.
    Oncogene. 2003 Nov 24;22(53):8634-44 PMID: 14634625
  25. Death receptor-induced cell killing.
    Cell Signal. 2004 Feb;16(2):139-44 PMID: 14636884
  26. Interaction with a membrane surface triggers a reversible conformational change in Bax normally associated with induction of apoptosis.
    J Biol Chem. 2003 Dec 5;278(49):48935-41 PMID: 14522999
  27. PKCmu prevents CD95-mediated apoptosis and enhances proliferation in pancreatic tumour cells.
    Oncogene. 2003 Dec 4;22(55):8939-47 PMID: 14654790
  28. Hepatocyte growth factor protects against hypoxia/reoxygenation-induced apoptosis in endothelial cells.
    J Biol Chem. 2004 Feb 13;279(7):5237-43 PMID: 14625309
  29. Golgi fragmentation during Fas-mediated apoptosis is associated with the rapid loss of GM130.
    Biochem Biophys Res Commun. 2004 Mar 26;316(1):6-11 PMID: 15003503
  30. Protein kinase C-dependent activation of P44/42 mitogen-activated protein kinase and heat shock protein 70 in signal transduction during hepatocyte ischemic preconditioning.
    World J Gastroenterol. 2004 Apr 1;10(7):1019-27 PMID: 15052686
  31. c-FLIP mediates resistance of Hodgkin/Reed-Sternberg cells to death receptor-induced apoptosis.
    J Exp Med. 2004 Apr 19;199(8):1041-52 PMID: 15078899
  32. FLIP protein and TRAIL-induced apoptosis.
    Vitam Horm. 2004;67:189-206 PMID: 15110178
  33. The phosphorylation status and anti-apoptotic activity of Bcl-2 are regulated by ERK and protein phosphatase 2A on the mitochondria.
    FEBS Lett. 2004 Jul 2;569(1-3):249-55 PMID: 15225643
  34. Myocyte and endothelial injury with ischemia reperfusion in isolated rat hearts.
    Am J Physiol. 1987 Jun;252(6 Pt 2):H1211-7 PMID: 3109261
  35. Clinical aspects of hypoxic pulmonary vasoconstriction.
    Exp Physiol. 1995 Sep;80(5):865-75 PMID: 8546875
  36. Intracellular ATP levels determine cell death fate by apoptosis or necrosis.
    Cancer Res. 1997 May 15;57(10):1835-40 PMID: 9157970
  37. The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury.
    Thromb Haemost. 1997 Jul;78(1):310-4 PMID: 9198172
  38. Oxidative stress and hypoxia/reoxygenation trigger CD95 (APO-1/Fas) ligand expression in microglial cells.
    FEBS Lett. 1998 Jun 5;429(1):67-72 PMID: 9657385
  39. Mutagenesis of the BH3 domain of BAX identifies residues critical for dimerization and killing.
    Mol Cell Biol. 1998 Oct;18(10):6083-9 PMID: 9742125
  40. Regulated targeting of BAX to mitochondria.
    J Cell Biol. 1998 Oct 5;143(1):207-15 PMID: 9763432
  41. Mechanisms of cell death in hypoxia/reoxygenation injury.
    Oncogene. 1998 Dec 24;17(25):3341-9 PMID: 9916996
  42. Role of hypoxia-induced Bax translocation and cytochrome c release in reoxygenation injury.
    Oncogene. 1998 Dec 31;17(26):3401-15 PMID: 10030664
  43. Cell death attenuation by 'Usurpin', a mammalian DED-caspase homologue that precludes caspase-8 recruitment and activation by the CD-95 (Fas, APO-1) receptor complex.
    Cell Death Differ. 1998 Apr;5(4):271-88 PMID: 10200473
  44. Protein kinase C inhibits CD95 (Fas/APO-1)-mediated apoptosis by at least two different mechanisms in Jurkat T cells.
    J Immunol. 1999 Nov 1;163(9):4737-46 PMID: 10528172
Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.11.4742-4751.2005
Published
2005-06-00
Pages
4742-51
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1140634
Subset
IM
Grants
NHLBI NIH HHS · R01 HL060234 · United States
NHLBI NIH HHS · R01-HL55330 · United States
NHLBI NIH HHS · R01-HL60234 · United States
NHLBI NIH HHS · R01 HL055330 · United States
NIAID NIH HHS · R01-AI42365 · United States
External Links
PubMed source DOI: 10.1128/MCB.25.11.4742-4751.2005 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2