Modulation of the mevalonate pathway by AKT regulates macrophage survival and development of pulmonary fibrosis

Journal of Biological Chemistry

Volumn 289, Issue 52, 2014, Pages 36204-36219

  Larson Casey, Jennifer L ^a   Murthy, Shubha ^a   Ryan, Alan J ^a   Brent Carter, A ^a,b,c  

^a UNIVERSITY OF IOWA   (United States)

^b UNIVERSITY OF IOWA   (United States)

^c Iowa City Veterans Affairs Health Care System   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACIDS; CELL DEATH; CHEMICAL ACTIVATION; ENZYMES; MAMMALS; MODULATION; PROTEINS;

ALVEOLAR MACROPHAGES; DECARBOXYLASES; GTP-BINDING PROTEINS; INDUCED APOPTOSIS; MEVALONATE PATHWAY; MULTIPLE CELLULAR PROCESS; PROTEIN KINASE B; PULMONARY FIBROSIS;

MACROPHAGES;

CARBOXYLYASE; CASPASE 3; CASPASE 9; MEVALONATE DIPHOSPHATE DECARBOXYLASE; MEVALONIC ACID; PROTEIN KINASE B; RAC1 PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; UNCLASSIFIED DRUG; AKT1 PROTEIN, MOUSE; HYDROGEN PEROXIDE; NEUROPEPTIDE; RAC1 PROTEIN, MOUSE; TGFB1 PROTEIN, MOUSE; TRANSFORMING GROWTH FACTOR BETA1;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; APOPTOSIS; ARTICLE; CELL SURVIVAL; CONTROLLED STUDY; ENZYME ACTIVATION; ENZYME ACTIVITY; ENZYME PHOSPHORYLATION; ENZYME REGULATION; GERANYLGERANYLATION; HUMAN; HUMAN CELL; LUNG ALVEOLUS MACROPHAGE; LUNG FIBROSIS; MOLECULAR MECHANICS; MOUSE; NONHUMAN; NORMAL HUMAN; OXIDATIVE STRESS; PROTEIN PROCESSING; SIGNAL TRANSDUCTION; 129 MOUSE; AMINO ACID SEQUENCE; ANIMAL; BIOSYNTHESIS; C57BL MOUSE; CELL CULTURE; CELL POLARITY; ENZYMOLOGY; IMMUNOLOGY; METABOLISM; MITOCHONDRION; PHOSPHORYLATION; PHYSIOLOGY; TRANSGENIC MOUSE;

MUS;

AMINO ACID SEQUENCE; ANIMALS; BIOSYNTHETIC PATHWAYS; CELL POLARITY; CELL SURVIVAL; CELLS, CULTURED; ENZYME ACTIVATION; HUMANS; HYDROGEN PEROXIDE; MACROPHAGES, ALVEOLAR; MEVALONIC ACID; MICE, 129 STRAIN; MICE, INBRED C57BL; MICE, TRANSGENIC; MITOCHONDRIA; NEUROPEPTIDES; OXIDATIVE STRESS; PHOSPHORYLATION; PROTEIN PROCESSING, POST-TRANSLATIONAL; PROTO-ONCOGENE PROTEINS C-AKT; PULMONARY FIBROSIS; RAC1 GTP-BINDING PROTEIN; TRANSFORMING GROWTH FACTOR BETA1;

EID: 84919934386     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.593285     Document Type: Article

References (76)

1. Datta, S. R., Brunet, A., and Greenberg, M. E. (1999) Cellular survival: a play in three Akts. Genes Dev. 13, 2905-2927
2. Zha, J., Harada, H., Yang, E., Jockel, J., and Korsmeyer, S. J. (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-X(L). Cell 87, 619-628
3. Datta, S. R., Dudek, H., Tao, X., Masters, S., Fu, H., Gotoh, Y., and Greenberg, M. E. (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231-241
4. Cardone, M. H., Roy, N., Stennicke, H. R., Salvesen, G. S., Franke, T. F., Stanbridge, E., Frisch, S., and Reed, J. C. (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282, 1318-1321
5. Pommier, Y., Sordet, O., Antony, S., Hayward, R. L., and Kohn, K. W. (2004) Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 23, 2934-2949
6. Zhou, B. P., Liao, Y., Xia, W., Zou, Y., Spohn, B., and Hung, M. C. (2001) HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation. Nat. Cell Biol. 3, 973-982
7. Mayo, L. D., and Donner, D. B. (2001) A phosphatidylinositol 3-kinase/ Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc. Natl. Acad. Sci. U.S.A. 98, 11598-11603
8. Cho, H., Mu, J., Kim, J. K., Thorvaldsen, J. L., Chu, Q., Crenshaw, E. B., 3rd, Kaestner, K. H., Bartolomei, M. S., Shulman, G. I., and Birnbaum, M. J. (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB -). Science 292, 1728-1731
9. Humbert, S., Bryson, E. A., Cordelières, F. P., Connors, N. C., Datta, S. R., Finkbeiner, S., Greenberg, M. E., and Saudou, F. (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev. Cell 2, 831-837
10. Huang, J. F., Chuang, Y. H., Dai, C. Y., Yu, M. L., Huang, C. F., Hsiao, P. J., Hsieh, M. Y., Huang, C. I., Yeh, M. L., Yang, J. F., Lin, Z. Y., Chen, S. C., and Chuang, W. L. (2011) Hepatic Akt expression correlates with advanced fibrosis in patients with chronic hepatitis C infection. Hepatol. Res. 41, 430-436
11. Lu, Y., Azad, N., Wang, L., Iyer, A. K., Castranova, V., Jiang, B. H., and Rojanasakul, Y. (2010) Phosphatidylinositol-3-kinase/akt regulates bleo-mycin-induced fibroblast proliferation and collagen production. Am. J. Respir. Cell Mol. Biol. 42, 432-441
12. Li, L. F., Liao, S. K., Huang, C. C., Hung, M. J., and Quinn, D. A. (2008) Serine/threonine kinase-protein kinase B and extracellular signal-regulated kinase regulate ventilator-induced pulmonary fibrosis after bleomy-cin-induced acute lung injury: a prospective, controlled animal experiment. Crit. Care 12, R103
13. Xia, H., Diebold, D., Nho, R., Perlman, D., Kleidon, J., Kahm, J., Avdulov, S., Peterson, M., Nerva, J., Bitterman, P., and Henke, C. (2008) Pathological integrin signaling enhances proliferation of primary lung fibroblasts from patients with idiopathic pulmonary fibrosis. J. Exp. Med. 205, 1659-1672
14. Vittal, R., Horowitz, J. C., Moore, B. B., Zhang, H., Martinez, F. J., Toews, G. B., Standiford, T. J., and Thannickal, V. J. (2005) Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury. Am. J. Pathol. 166, 367-375
15. Le Cras, T. D., Korfhagen, T. R., Davidson, C., Schmidt, S., Fenchel, M., Ikegami, M., Whitsett, J. A., and Hardie, W. D. (2010) Inhibition of PI3K by PX-866 prevents transforming growth factor-α-induced pulmonary fibrosis. 176,
16. Carano, A., Teitelbaum, S. L., Konsek, J. D., Schlesinger, P. H., and Blair, H. C. (1990) Bisphosphonates directly inhibit the bone resorption activity of isolated avian osteoclasts in vitro. J. Clin. Invest. 85, 456-461
17. Gardner, M. J., Hall, N., Fung, E., White, O., Berriman, M., Hyman, R. W., Carlton, J. M., Pain, A., Nelson, K. E., Bowman, S., Paulsen, I. T., James, K., Eisen, J. A., Rutherford, K., Salzberg, S. L., Craig, A., Kyes, S., Chan, M. S., Nene, V., Shallom, S. J., Suh, B., Peterson, J., Angiuoli, S., Pertea, M., Allen, J., Selengut, J., Haft, D., Mather, M. W., Vaidya, A. B., Martin, D. M., Fairlamb, A. H., Fraunholz, M. J., Roos, D. S., Ralph, S. A., McFadden, G. I., Cummings, L. M., Subramanian, G. M., Mungall, C., Venter, J. C., Carucci, D. J., Hoffman, S. L., Newbold, C., Davis, R. W., Fraser, C. M., and Barrell, B. (2002) Genome sequence of the human malaria parasite Plasmodium falciparum. Nature 419, 498-511
18. del Real, G., Jiménez-Baranda, S., Mira, E., Lacalle, R. A., Lucas, P., Gómez-Moutón, C., Alegret, M., Peňa, J. M., Rodríguez-Zapata, M., Alvarez-Mon, M., Martínez, A. C., and Maňes, S. (2004) Statins inhibit HIV-1 infection by down-regulating Rho activity. J. Exp. Med. 200, 541-547
19. Jiang, K., Coppola, D., Crespo, N. C., Nicosia, S. V., Hamilton, A. D., Sebti, S. M., and Cheng, J. Q. (2000) The phosphoinositide 3-OH kinase/AKT2 pathway as a critical target for farnesyltransferase inhibitor-induced apoptosis. Mol. Cell. Biol. 20, 139-148
20. Kazi, A., Carie, A., Blaskovich, M. A., Bucher, C., Thai, V., Moulder, S., Peng, H., Carrico, D., Pusateri, E., Pledger, W. J., Berndt, N., Hamilton, A., and Sebti, S. M. (2009) Blockade of protein geranylgeranylation inhibits Cdk2-dependent p27Kip1 phosphorylation on Thr187 and accumulates p27Kip1 in the nucleus: implications for breast cancer therapy. Mol. Cell. Biol. 29, 2254-2263
21. Sun, J., Ohkanda, J., Coppola, D., Yin, H., Kothare, M., Busciglio, B., Hamilton, A. D., and Sebti, S. M. (2003) Geranylgeranyltransferase I inhibitor GGTI-2154 induces breast carcinoma apoptosis and tumor regression in H-Ras transgenic mice. Cancer Res. 63, 8922-8929
22. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D., and Hall, A. (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70, 401-410
23. Reiss, Y., Goldstein, J. L., Seabra, M. C., Casey, P. J., and Brown, M. S. (1990) Inhibition of purified p21ras farnesyl:protein transferase by Cys-AAX tetrapeptides. Cell 62, 81-88
24. Osborn-Heaford, H. L., Ryan, A. J., Murthy, S., Racila, A. M., He, C., Sieren, J. C., Spitz, D. R., and Carter, A. B. (2012) Mitochondrial Rac1 GTPase import and electron transfer from cytochrome c are required for pulmonary fibrosis. J. Biol. Chem. 287, 3301-3312
25. Chen, Z., Sun, J., Pradines, A., Favre, G., Adnane, J., and Sebti, S. M. (2000) Both farnesylated and geranylgeranylated RhoB inhibit malignant transformation and suppress human tumor growth in nude mice. J. Biol. Chem. 275, 17974-17978
26. Du, W., and Prendergast, G. C. (1999) Geranylgeranylated RhoB mediates suppression of human tumor cell growth by farnesyltransferase inhibitors. Cancer Res. 59, 5492-5496
27. Miquel, K., Pradines, A., Sun, J., Qian, Y., Hamilton, A. D., Sebti, S. M., and Favre, G. (1997) GGTI-298 induces G0-G1 block and apoptosis, whereas FTI-277 causes G2-M enrichment in A549 cells. Cancer Res. 57, 1846-1850
28. Hawkins, P. T., Eguinoa, A., Qiu, R. G., Stokoe, D., Cooke, F. T., Walters, R., Wennstro?m, S., Claesson-Welsh, L., Evans, T., and Symons, M. (1995) PDGF stimulates an increase in GTP-Rac via activation of phosphoinositide 3-kinase. Curr. Biol. 5, 393-403
29. Xue, Y., Li, N. L., Yang, J. Y., Chen, Y., Yang, L. L., and Liu, W. C. (2011) Phosphatidylinositol 3'-kinase signaling pathway is essential for Rac1-induced hypoxia-inducible factor-1- and vascular endothelial growth factor expression. Am. J. Physiol. Heart Circ. Physiol. 300, H2169-H2176
30. Ozaki, M., Haga, S., Zhang, H. Q., Irani, K., and Suzuki, S. (2003) Inhibition of hypoxia/reoxygenation-induced oxidative stress in HGF-stimulated antiapoptotic signaling: role of PI3-K and Akt kinase upon rac1. Cell Death Differ. 10, 508-515
31. Kwon, T., Kwon, D. Y., Chun, J., Kim, J. H., and Kang, S. S. (2000) Akt protein kinase inhibits Rac1-GTP binding through phosphorylation at serine 71 of Rac1. J. Biol. Chem. 275, 423-428
32. Kuijk, L. M., Beekman, J. M., Koster, J., Waterham, H. R., Frenkel, J., and Coffer, P. J. (2008) HMG-CoA reductase inhibition induces IL-1- release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 112, 3563-3573
33. Lin, C. H., Cheng, H. W., Ma, H. P., Wu, C. H., Hong, C. Y., and Chen, B. C. (2011) Thrombin induces NF-B activation and IL-8/CXCL8 expression in lung epithelial cells by a Rac1-dependent PI3K/Akt pathway. J. Biol. Chem. 286, 10483-10494
34. Murthy, S., Ryan, A., He, C., Mallampalli, R. K., and Carter, A. B. (2010) Rac1-mediated mitochondrial H2O2 generation regulates MMP-9 gene expression in macrophages via inhibition of SP-1 and AP-1. J. Biol. Chem. 285, 25062-25073
35. 2 generation. J. Biol. Chem. 286, 15597-15607
36. Tephly, L. A., and Carter, A. B. (2007) Constitutive NADPH oxidase and increased mitochondrial respiratory chain activity regulate chemokine gene expression. Am. J. Physiol. Lung Cell Mol. Physiol. 293, L1143-L1155
37. Shull, L. W., Wiemer, A. J., Hohl, R. J., and Wiemer, D. F. (2006) Synthesis and biological activity of isoprenoid bisphosphonates. Bioorg. Med. Chem. 14, 4130-4136
38. Wasko, B. M., Dudakovic, A., and Hohl, R. J. (2011) Bisphosphonates induce autophagy by depleting geranylgeranyl diphosphate. J. Pharmacol. Exp. Ther. 337, 540-546
39. Murthy, S., Adamcakova-Dodd, A., Perry, S. S., Tephly, L. A., Keller, R. M., Metwali, N., Meyerholz, D. K., Wang, Y., Glogauer, M., Thorne, P. S., and Carter, A. B. (2009) Modulation of reactive oxygen species by Rac1 or catalase prevents asbestos-induced pulmonary fibrosis. Am. J. Physiol. Lung Cell Mol. Physiol. 297, L846-L855
40. He, C., Ryan, A. J., Murthy, S., and Carter, A. B. (2013) Accelerated development of pulmonary fibrosis via Cu,Zn-superoxide dismutase-induced alternative activation of macrophages. J. Biol. Chem. 288, 20745-20757
41. Carmona, G., Göttig, S., Orlandi, A., Scheele, J., Bäuerle, T., Jugold, M., Kiessling, F., Henschler, R., Zeiher, A. M., Dimmeler, S., and Chavakis, E. (2009) Role of the small GTPase Rap1 for integrin activity regulation in endothelial cells and angiogenesis. Blood 113, 488-497
42. Zins, K., Lucas, T., Reichl, P., Abraham, D., and Aharinejad, S. (2013) A Rac1/Cdc42 GTPase-specific small molecule inhibitor suppresses growth of primary human prostate cancer xenografts and prolongs survival in mice. PLoS One 8, e74924
43. Guo, F., Cancelas, J. A., Hildeman, D., Williams, D. A., and Zheng, Y. (2008) Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 112, 1767-1775
44. Zeng, P. Y., Rane, N., Du, W., Chintapalli, J., and Prendergast, G. C. (2003) Role for RhoB and PRK in the suppression of epithelial cell transformation by farnesyltransferase inhibitors. Oncogene 22, 1124-1134
45. Goldstein, J. L., and Brown, M. S. (1990) Regulation of the mevalonate pathway. Nature 343, 425-430
46. Dan, H. C., Jiang, K., Coppola, D., Hamilton, A., Nicosia, S. V., Sebti, S. M., and Cheng, J. Q. (2004) Phosphatidylinositol-3-OH kinase/AKT and survivin pathways as critical targets for geranylgeranyltransferase I inhibitorinduced apoptosis. Oncogene 23, 706-715
47. Arranz, A., Doxaki, C., Vergadi, E., Martinez de la Torre, Y., Vaporidi, K., Lagoudaki, E. D., Ieronymaki, E., Androulidaki, A., Venihaki, M., Margioris, A. N., Stathopoulos, E. N., Tsichlis, P. N., and Tsatsanis, C. (2012) Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc. Natl. Acad. Sci. U.S.A. 109, 9517-9522
48. Rauh, M. J., Ho, V., Pereira, C., Sham, A., Sly, L. M., Lam, V., Huxham, L., Minchinton, A. I., Mui, A., and Krystal, G. (2005) SHIP represses the generation of alternatively activated macrophages. Immunity 23, 361-374
49. Martin, M., Schifferle, R. E., Cuesta, N., Vogel, S. N., Katz, J., and Michalek, S. M. (2003) Role of the phosphatidylinositol 3 kinase-Akt pathway in the regulation of IL-10 and IL-12 by Porphyromonas gingivalis lipopolysaccharide. J. Immunol. 171, 717-725
50. Jain, M., Rivera, S., Monclus, E. A., Synenki, L., Zirk, A., Eisenbart, J., Feghali-Bostwick, C., Mutlu, G. M., Budinger, G. R., and Chandel, N. S. (2013) Mitochondrial reactive oxygen species regulate transforming growth factor-β signaling. J. Biol. Chem. 288, 770-777
51. Chensue, S. W., Warmington, K., Ruth, J. H., Lukacs, N., and Kunkel, S. L. (1997) Mycobacterial and schistosomal antigen-elicited granuloma formation in IFN-gamma and IL-4 knockout mice: analysis of local and regional cytokine and chemokine networks. J. Immunol. 159, 3565-3573
52. Daley, J. M., Brancato, S. K., Thomay, A. A., Reichner, J. S., and Albina, J. E. (2010) The phenotype of murine wound macrophages. J Leukoc. Biol. 87, 59-67
53. Duffield, J. S., Forbes, S. J., Constandinou, C. M., Clay, S., Partolina, M., Vuthoori, S., Wu, S., Lang, R., and Iredale, J. P. (2005) Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J. Clin. Invest. 115, 56-65
54. Pechkovsky, D. V., Prasse, A., Kollert, F., Engel, K. M., Dentler, J., Luttmann, W., Friedrich, K., Müller-Quernheim, J., and Zissel, G. (2010) Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin. Immunol. 137, 89-101
55. Shechter, R., Miller, O., Yovel, G., Rosenzweig, N., London, A., Ruckh, J., Kim, K. W., Klein, E., Kalchenko, V., Bendel, P., Lira, S. A., Jung, S., and Schwartz, M. (2013) Recruitment of beneficialM2macrophages to injured spinal cord is orchestrated by remote brain choroid plexus. Immunity 38, 555-569
56. Nogueira, V., Park, Y., Chen, C. C., Xu, P. Z., Chen, M. L., Tonic, I., Unterman, T., and Hay, N. (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14, 458-470
57. Dolado, I., and Nebreda, A. R. (2008) AKT and oxidative stress team up to kill cancer cells. Cancer Cell 14, 427-429
58. Hollander, M. C., Maier, C. R., Hobbs, E. A., Ashmore, A. R., Linnoila, R. I., and Dennis, P. A. (2011) Akt1 deletion prevents lung tumorigenesis by mutant K-ras. Oncogene 30, 1812-1821
59. Vasudevan, K. M., and Garraway, L. A. (2010)AKTsignaling in physiology and disease. Curr. Top. Microbiol. Immunol. 347, 105-133
60. Chang, H. W., Aoki, M., Fruman, D., Auger, K. R., Bellacosa, A., Tsichlis, P. N., Cantley, L. C., Roberts, T. M., and Vogt, P. K. (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276, 1848-1850
61. Chen, H. K., Fernandez-Funez, P., Acevedo, S. F., Lam, Y. C., Kaytor, M. D., Fernandez, M. H., Aitken, A., Skoulakis, E. M., Orr, H. T., Botas, J., and Zoghbi, H. Y. (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113, 457-468
62. Georgescu, M. M., Kirsch, K. H., Akagi, T., Shishido, T., and Hanafusa, H. (1999) The tumor-suppressor activity of PTEN is regulated by its carbox-yl-terminal region. Proc. Natl. Acad. Sci. U.S.A. 96, 10182-10187
63. Samuels, Y., Diaz, L. A., Jr., Schmidt-Kittler, O., Cummins, J. M., Delong, L., Cheong, I., Rago, C., Huso, D. L., Lengauer, C., Kinzler, K. W., Vogelstein, B., and Velculescu, V. E. (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561-573
64. Danesh, F. R., Sadeghi, M. M., Amro, N., Philips, C., Zeng, L., Lin, S., Sahai, A., and Kanwar, Y. S. (2002) 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors prevent high glucose-induced proliferation of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: Implications for diabetic nephropathy. Proc. Natl. Acad. Sci. U.S.A. 99, 8301-8305
65. Brodersen, P., Sakvarelidze-Achard, L., Schaller, H., Khafif, M., Schott, G., Bendahmane, A., and Voinnet, O. (2012) Isoprenoid biosynthesis is required for miRNA function and affects membrane association of ARGONAUTE1 in Arabidopsis. Proc. Natl. Acad. Sci. U.S.A. 109, 1778-1783
66. Chung, C. Y., Potikyan, G., and Firtel, R. A. (2001) Control of cell polarity and chemotaxis by Akt/PKB and PI3 kinase through the regulation of PAKa. Mol. Cell 7, 937-947
67. Tang, Y., Zhou, H., Chen, A., Pittman, R. N., and Field, J. (2000) The Akt proto-oncogene links Ras to Pak and cell survival signals. J. Biol. Chem. 275, 9106-9109
68. Rodriguez-Viciana, P., Warne, P. H., Khwaja, A., Marte, B. M., Pappin, D., Das, P., Waterfield, M. D., Ridley, A., and Downward, J. (1997) Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89, 457-467
69. Rosenson, R. S., and Tangney, C. C. (1998) Antiatherothrombotic properties of statins: implications for cardiovascular event reduction. JAMA 279, 1643-1650
70. Wong, W. B., Lin, V. W., Boudreau, D., and Devine, E. B. (2013) Statins in the prevention of dementia and Alzheimer's disease: a meta-analysis of observational studies and an assessment of confounding. Pharmacoepidemiol. Drug Saf. 22, 345-358
71. Merx, M. W., Liehn, E. A., Graf, J., van de Sandt, A., Schaltenbrand, M., Schrader, J., Hanrath, P., and Weber, C. (2005) Statin treatment after onset of sepsis in a murine model improves survival. Circulation 112, 117-124
72. Krepkiy, D., and Miziorko, H. M. (2004) Identification of active site residues in mevalonate diphosphate decarboxylase: implications for a family of phosphotransferases. Protein Sci. 13, 1875-1881
73. Dephoure, N., Zhou, C., Villén, J., Beausoleil, S. A., Bakalarski, C. E., Elledge, S. J., and Gygi, S. P. (2008) A quantitative atlas of mitotic phosphorylation. Proc. Natl. Acad. Sci. U.S.A. 105, 10762-10767
74. Obata, T., Yaffe, M. B., Leparc, G. G., Piro, E. T., Maegawa, H., Kashiwagi, A., Kikkawa, R., and Cantley, L. C. (2000) Peptide and protein library screening defines optimal substrate motifs for AKT/PKB. J. Biol. Chem. 275, 36108-36115
75. Redente, E. F., Keith, R. C., Janssen, W., Henson, P. M., Ortiz, L. A., Downey, G. P., Bratton, D. L., and Riches, D. W. (2014) Tumor necrosis factor-α accelerates the resolution of established pulmonary fibrosis in mice by targeting profibrotic lung macrophages. Am. J. Respir. Cell Mol. Biol. 50, 825-837
76. Weigert, A., Johann, A. M., von Knethen, A., Schmidt, H., Geisslinger, G., and Bru?ne, B. (2006) Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood 108, 1635-1642