Autophagy in toxicology: Cause or consequence?

Annual Review of Pharmacology and Toxicology

Volumn 53, Issue , 2013, Pages 275-297

  Orrenius, Sten ^a   Kaminskyy, Vitaliy O ^a   Zhivotovsky, Boris ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

Author keywords

apoptosis; ATG; autophagic cell death; autophagy related disease; mitophagy; toxicity

Indexed keywords

TOXIC SUBSTANCE;

AUTOPHAGY; CARDIOVASCULAR DISEASE; CELL DEATH; CELL ORGANELLE; CELL SURVIVAL; CHAPERONE MEDIATED AUTOPHAGY; DEGENERATIVE DISEASE; HUMAN; LIVER DISEASE; MACROAUTOPHAGY; MICROAUTOPHAGY; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; REVIEW; TOXICOLOGY;

ANIMALS; AUTOPHAGY; CELL DEATH; HAZARDOUS SUBSTANCES; HOMEOSTASIS; HUMANS;

EID: 84872256740     PISSN: 03621642     EISSN: 15454304     Source Type: Book Series    
DOI: 10.1146/annurev-pharmtox-011112-140210     Document Type: Review

References (131)

1. Stromhaug PE, Klionsky DJ. 2001. Approaching the molecular mechanism of autophagy. Traffic 2:524-31
2. Kroemer G, Galuzzi L, Vandenabeele P, Abrams J, Alnemri EH, et al. 2009. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ. 16:3-11
3. Mizushima N. 2007. Autophagy: process and function. Genes Dev. 21:2861-73
4. Levine B, Kroemer G. 2008. Autophagy in the pathogenesis of disease. Cell 132:27-42
5. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. 2009. Dynamics and diversity in autophagymechanisms: lessons from yeast. Nat. Rev. Mol. Cell Biol. 10:458-67
6. Levine B, Mizushima N, VirginHW. 2011. Autophagy in immunity and inflammation. Nature 469:323-35
7. Mizushima N, Komatsu M. 2011. Autophagy: renovation of cells and tissues. Cell 147:728-41
8. Mizushima N, Noda T, Yoshimori T, Tanaka Y, Ishii T, et al. 1998. A protein conjugation system essential for autophagy. Nature 395:395-98
9. Mizushima N, Noda T, Ohsumi Y. 1999. Apg16p is required for the function of the Apg12p-Apg5p conjugate in the yeast autophagy pathway. EMBO J. 18:3888-96
10. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, et al. 2000. A ubiquitin-like system mediates protein lipidation. Nature 408:488-92
11. Dice JF. 2007. Chaperone-mediated autophagy. Autophagy 3:295-99
12. Cuervo AM. 2010. Chaperone-mediated autophagy: selectivity pays off. Trends Endocrinol.Metab. 21:142-50
13. Chiang HL, Dice JF. 1988. Peptide sequences that target proteins for enhanced degradation during serum withdrawal. J. Biol. Chem. 263:6797-805
14. Cuervo AM, Dice JF. 1996. A receptor for the selective uptake and degradation of proteins by lysosomes. Science 273:501-3
15. Kaushik S, Bandyopadhyay U, Sridhar S, KiffinR, Martinez-Vicente M, et al. 2011. Chaperone-mediated autophagy at a glance. J. Cell Sci. 124:495-99
16. Sahu R, Kaushik S, Clement CC, Cannizzo ES, Scharf B, et al. 2011. Microautophagy of cytosolic proteins by late endosomes. Dev. Cell 20:131-39
17. Mathew R, Karp CM, Beaudoin B, Vuong N, Chen G, et al. 2009. Autophagy suppresses tumorigenesis through elimination of p62. Cell 137:1062-75
18. Chen HY, White E. 2011. Role of autophagy in cancer prevention. Cancer Prev. Res. 4:973-83
19. Narendra D, Tanaka A, Suen DF, YouleRJ. 2008. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. J. Cell Biol. 183:795-803
20. Hyun DH, Lee M, Hattori N, Kubo S, Mizuno Y, et al. 2002. Effect of wild-type or mutant Parkin on oxidative damage, nitric oxide, antioxidant defenses, and the proteasome. J. Biol. Chem. 277:28572-77
21. Vives-Bauza C, Zhou C, Huang Y, Cui M, de Vries RL, et al. 2010. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl. Acad. Sci. USA 107:378-83
22. Matsuda N, Sato S, Shiba K, Okatsu K, Saisho K, et al. 2010. PINK1 stabilized by mitochondrial depolarization recruits Parkin to damaged mitochondria and activates latent Parkin for mitophagy. J. Cell Biol. 189:211-21
23. Wang X, Winter D, Ashrafi G, Schlehe J, Wong YL, et al. 2011. PINK1 and Parkin target Miro for phosphorylation and degradation to arrest mitochondrial motility. Cell 147:893-906
24. Schweers RL, Zhang J, Randall MS, Loyd MR, Li W, et al. 2007. NIX is required for programmed mitochondrial clearance during reticulocyte maturation. Proc. Natl. Acad. Sci. USA 104:19500-5
25. Sandoval H, Thiagarajan P, Dasgupta SK, Schumacher A, Prchal JT, et al. 2008. Essential role for Nix in autophagic maturation of erythroid cells. Nature 454:232-35
26. SchwartenM, Mohrluder J, Ma P, Stoldt M, Thielmann Y, et al. 2009. Nix directly binds to GABARAP: a possible crosstalk between apoptosis and autophagy. Autophagy 5:690-98
27. Novak I, Kirkin V, McEwan DG, Zhang J, Wild P, et al. 2010. Nix is a selective autophagy receptor for mitochondrial clearance. EMBO Rep. 11:45-51
28. Soubannier V, McLelland GL, Zunino R, Braschi E, Rippstein P, et al. 2012. A vesicular transport pathway shuttles cargo from mitochondria to lysosomes. Curr. Biol. 22:135-41
29. Kundu M, Lindsten T, Yang CY, Wu J, Zhao F, et al. 2008. Ulk1 plays a critical role in the autophagic clearance of mitochondria and ribosomes during reticulocyte maturation. Blood 112:1493-502
30. Iwata J, Ezaki J, Komatsu M, Yokota S, Ueno T, et al. 2006. Excess peroxisomes are degraded by autophagic machinery in mammals. J. Biol. Chem. 281:4035-41
31. Hara-Kuge S, Fujiki Y. 2008. The peroxin Pex14p is involved in LC3-dependent degradation of mammalian peroxisomes. Exp. Cell. Res. 314:3531-41
32. Ezaki J, Kominami E, Ueno T. 2011. Peroxisome degradation in mammals. IUBMB Life 63:1001-8
33. Kuma A, Mizushima N. 2010. Physiological role of autophagy as an intracellular recycling system: with an emphasis on nutrient metabolism. Semin. Cell Dev. Biol. 21:683-90
34. Tsukamoto S, Kuma A, MurakamiM, Kishi C, Yamamoto A, Mizushima N. 2008. Autophagy is essential for preimplantation development of mouse embryos. Science 321:117-20
35. Mizushima N, Levine B. 2010. Autophagy inmammalian development and differentiation. Nat. Cell Biol. 12:823-30
36. Yue Z, Jin S, Yang C, Levine AJ, Heintz N. 2003. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc. Natl. Acad. Sci. USA 100:15077-82
37. Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, et al. 2007. Ambra1 regulates autophagy and development of the nervous system. Nature 447:1121-25
38. Gan B, Peng X, Nagy T, Alcaraz A, Gu H, Guan JL. 2006. Role of FIP200 in cardiac and liver development and its regulation of TNFαand TSC-mTOR signaling pathways. J. Cell Biol. 175:121-33
39. Nishida Y, Arakawa S, Fujitani K, Yamaguchi H, Mizuta T, et al. 2009. Discovery of Atg5/Atg7-independent alternative macroautophagy. Nature 461:654-58
40. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, et al. 2004. The role of autophagy during the early neonatal starvation period. Nature 432:1032-36
41. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, et al. 2005. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J. Cell Biol. 169:425-34
42. Saitoh T, Fujita N, Hayashi T, Takahara K, Satoh T, et al. 2009. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl. Acad. Sci. USA 106:20842-46
43. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, et al. 2008. Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1βproduction. Nature 456:264-68
44. Sou YS, Waguri S, Iwata J, Ueno T, Fujimura T, et al. 2008. TheAtg8 conjugation system is indispensable for proper development of autophagic isolation membranes in mice. Mol. Biol. Cell 19:4762-75
45. Miller BC, Zhao Z, Stephenson LM, Cadwell K, Pua HH, et al. 2008. The autophagy gene ATG5 plays an essential role in B lymphocyte development. Autophagy 4:309-14
46. Zhao Y, Chen G, Zhang W, Xu N, Zhu JY, et al. 2012. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1α/BNIP3 signaling pathway. J. Cell. Physiol. 227:639-48
47. Zhang Y, Goldman S, Baerga R, Zhao Y, Komatsu M, Jin S. 2009. Adipose-specific deletion of autophagyrelated gene 7 (atg7) in mice reveals a role in adipogenesis. Proc. Natl. Acad. Sci. USA 106:19860-65
48. Aymard E, Barruche V, Naves T, Bordes S, Closs B, et al. 2011. Autophagy in human keratinocytes: an early step of the differentiation? Exp. Dermatol. 20:263-68
49. Zhang J, Liu J, Huang Y, Chang JY, Liu L, et al. 2012. FRS2α-mediated FGF signals suppress premature differentiation of cardiac stem cells through regulating autophagy activity. Circ. Res. 110:e29-39
50. Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, et al. 2003. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J. Clin. Investig. 112:1809-20
51. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, et al. 2007. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131:1149-63
52. Komatsu M, Kurokawa H, Waguri S, Taguchi K, Kobayashi A, et al. 2010. The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat. Cell Biol. 12:213-23
53. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, et al. 1997. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem. Biophys. Res. Commun. 236:313-22
54. Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, et al. 2011. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J. Am. Soc. Nephrol. 22:902-13
55. Hartleben B, Godel M, Meyer-Schwesinger C, Liu S, Ulrich T, et al. 2010. Autophagy influences glomerular disease susceptibility and maintains podocyte homeostasis in aging mice. J. Clin. Investig. 120:1084-96
56. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, et al. 2006. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441:885-89
57. Yuan J, Lipinski M, Degterev A. 2003. Diversity in the mechanisms of neuronal cell death. Neuron 40:401-13
58. Fleming A, Noda T, Yoshimori T, Rubinsztein DC. 2011. Chemical modulators of autophagy as biological probes and potential therapeutics. Nat. Chem. Biol. 7:9-17
59. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, et al. 2010. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol. Rev. 90:1383-435
60. Shimizu S, Kanaseki T, Mizushima N, Mizuta T, Arakawa-Kobayashi S, et al. 2004. Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes. Nat. Cell Biol. 6:1221-28
61. Djavaheri-Mergny M, Maiuri MC, Kroemer G. 2010. Cross talk between apoptosis and autophagy by caspase-mediated cleavage of Beclin 1. Oncogene 29:1717-19
62. Yousefi S, Perozzo R, Schmid I, Ziemiecki A, Schaffner T, et al. 2006. Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis. Nat. Cell Biol. 8:1124-32
63. Gao Z, Gammoh N, Wong PM, Erdjument-Bromage H, Tempst P, Jiang X. 2010. Processing of autophagic protein LC3 by the 20S proteasome. Autophagy 6:126-37
64. Kroemer G, Marino G, Levine B. 2010. Autophagy and the integrated stress response. Mol. Cell 40:280-93
65. DingWX, Ni HM, GaoW, Hou YF, Melan MA, et al. 2007. Differential effects of endoplasmic reticulum stress-induced autophagy on cell survival. J. Biol. Chem. 282:4702-10
66. Hoyer-Hansen M, Jaattela M. 2007. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ. 14:1576-82
67. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, et al. 2006. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol. Cell. Biol. 26:9220-31
68. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, et al. 2007. ER stress (PERK/eIF2αphosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ. 14:230-39
69. Sakaki K, Wu J, Kaufman RJ. 2008. Protein kinase Cθis required for autophagy in response to stress in the endoplasmic reticulum. J. Biol. Chem. 283:15370-80
70. Ganley IG, Wong PM, Gammoh N, Jiang X. 2011. Distinct autophagosomal-lysosomal fusion mechanism revealed by thapsigargin-induced autophagy arrest. Mol. Cell 42:731-43
71. Chen Y, Azad MB, Gibson SB. 2009. Superoxide is the major reactive oxygen species regulating autophagy. Cell Death Differ. 16:1040-52
72. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. 2007. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 26:1749-60
73. Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX. 2012. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 55:222-32
74. Kim EH, Sohn S, Kwon HJ, Kim SU, Kim MJ, et al. 2007. Sodium selenite induces superoxide-mediated mitochondrial damage and subsequent autophagic cell death in malignant glioma cells. Cancer Res. 67:6314-24
75. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, et al. 2005. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 122:927-39
76. Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, et al. 2007. Functional and physical interaction between Bcl-XL and a BH3-like domain in Beclin-1. EMBO J. 26:2527-39
77. Copetti T, BertoliC, Dalla E, Demarchi F, Schneider C. 2009. p65/RelA modulates BECN1 transcription and autophagy. Mol. Cell. Biol. 29:2594-608
78. Jiang Q, Wang Y, Li T, Shi K, Li Z, et al. 2011. Heat shock protein 90-mediated inactivation of nuclear factor-κB switches autophagy to apoptosis through becn1 transcriptional inhibition in selenite-induced NB4 cells. Mol. Biol. Cell 22:1167-80
79. Suen DF, Narendra DP, Tanaka A, Manfredi G, Youle RJ. 2010. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc. Natl. Acad. Sci. USA 107:11835-40
80. Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT. 2007. Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am. J. Pathol. 170:75-86
81. Fiorito F, Ciarcia R, Granato GE, Marfe G, Iovane V, et al. 2011. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin induced autophagy in a bovine kidney cell line. Toxicology 290:258-70
82. Csordas A, Kreutmayer S, Ploner C, Braun PR, Karlas A, et al. 2011. Cigarette smoke extract induces prolonged endoplasmic reticulum stress and autophagic cell death in human umbilical vein endothelial cells. Cardiovasc. Res. 92:141-48
83. Ryter SW, Choi AM. 2010. Autophagy in the lung. Proc. Am. Thorac. Soc. 7:13-21
84. Son YO, Wang X, Hitron JA, Zhang Z, Cheng S, et al. 2011. Cadmium induces autophagy through ROS-dependent activation of theLKB1-AMPKsignaling in skin epidermal cells. Toxicol. Appl. Pharmacol. 255:287-96
85. Chargui A, Zekri S, Jacquillet G, Rubera I, Ilie M, et al. 2011. Cadmium-induced autophagy in rat kidney: an early biomarker of subtoxic exposure. Toxicol. Sci. 121:31-42
86. Wang SH, Shih YL, Ko WC, Wei YH, Shih CM. 2008. Cadmium-induced autophagy and apoptosis are mediated by a calcium signaling pathway. Cell. Mol. Life Sci. 65:3640-52
87. Thoen LF, Guimaraes EL, Dolle L, Mannaerts I, Najimi M, et al. 2011. A role for autophagy during hepatic stellate cell activation. J. Hepatol. 55:1353-60
88. Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, et al. 2009. Autophagy regulates lipid metabolism. Nature 458:1131-35
89. Kanzawa T, Zhang L, Xiao L, Germano IM, Kondo Y, Kondo S. 2005. Arsenic trioxide induces autophagic cell death inmalignant glioma cells by upregulation ofmitochondrial cell death protein BNIP3. Oncogene 24:980-91
90. Yu L, Alva A, Su H, Dutt P, Freundt E, et al. 2004. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304:1500-2
91. Yu L, Wan F, Dutta S, Welsh S, Liu Z, et al. 2006. Autophagic programmed cell death by selective catalase degradation. Proc. Natl. Acad. Sci. USA 103:4952-57
92. Joo JH, Dorsey FC, Joshi A, Hennessy-Walters KM, Rose KL, et al. 2011. Hsp90-Cdc37 chaperone complex regulates Ulk1-and Atg13-mediated mitophagy. Mol. Cell 43:572-85
93. Chen Y, McMillan-Ward E, Kong J, Israels SJ, Gibson SB. 2007. Mitochondrial electron-transportchain inhibitors of complexes I and II induce autophagic cell death mediated by reactive oxygen species. J. Cell Sci. 120:4155-66
94. Kiffin R, Christian C, Knecht E, Cuervo AM. 2004. Activation of chaperone-mediated autophagy during oxidative stress. Mol. Biol. Cell 15:4829-40
95. Massey AC, Kaushik S, Sovak G, Kiffin R, Cuervo AM. 2006. Consequences of the selective blockage of chaperone-mediated autophagy. Proc. Natl. Acad. Sci. USA 103:5805-10
96. Pallet N, Bouvier N, Legendre C, Gilleron J, Codogno P, et al. 2008. Autophagy protects renal tubular cells against cyclosporine toxicity. Autophagy 4:783-91
97. Gozuacik D, Bialik S, Raveh T, Mitou G, Shohat G, et al. 2008. DAP-kinase is a mediator of endoplasmic reticulum stress-induced caspase activation and autophagic cell death. Cell Death Differ. 15:1875-86
98. Amaravadi RK, Lippincott-Schwartz J, Yin XM, Weiss WA, Takebe N, et al. 2011. Principles and current strategies for targeting autophagy for cancer treatment. Clin. Cancer Res. 17:654-66
99. Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, et al. 2007. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Investig. 117:326-36
100. Apel A, Herr I, Schwarz H, Rodemann HP, Mayer A. 2008. Blocked autophagy sensitizes resistant carcinoma cells to radiation therapy. Cancer Res. 68:1485-94
101. Xiong N, Jia M, Chen C, Xiong J, Zhang Z, et al. 2011. Potential autophagy enhancers attenuate rotenone-induced toxicity in SH-SY5Y. Neuroscience 199:292-302
102. Filomeni G, Graziani I, De Zio D, Dini L, Centonze D, et al. 2012. Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson's disease. Neurobiol. Aging 33:767-85
103. Dohi E, Tanaka S, Seki T, Miyagi T, Hide I, et al. 2012. Hypoxic stress activates chaperone-mediated autophagy and modulates neuronal cell survival. Neurochem. Int. 60:431-42
104. Carchman EH, Rao J, Loughran PA, Rosengart MR, Zuckerbraun BS. 2011. Heme oxygenase-1-mediated autophagy protects against hepatocyte cell death and hepatic injury from infection/sepsis in mice. Hepatology 53:2053-62
105. Li S, Zhou Y, Fan J, Cao S, Cao T, et al. 2011. Heat shock protein 72 enhances autophagy as a protective mechanism in lipopolysaccharide-induced peritonitis in rats. Am. J. Pathol. 179:2822-34
106. Swain SM, Whaley FS, Ewer MS. 2003. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer 97:2869-79
107. Lu L, Wu W, Yan J, Li X, Yu H, Yu X. 2009. Adriamycin-induced autophagic cardiomyocyte death plays a pathogenic role in a rat model of heart failure. Int. J. Cardiol. 134:82-90
108. Kobayashi S, Volden P, Timm D, Mao K, Xu X, Liang Q. 2010. Transcription factor GATA4 inhibits doxorubicin-induced autophagy and cardiomyocyte death. J. Biol. Chem. 285:793-804
109. Kundu M, Thompson CB. 2008. Autophagy: basic principles and relevance to disease. Annu. Rev. Pathol. Mech. Dis. 3:427-55
110. Florez-McClure ML, Linseman DA, Chu CT, Barker PA, Bouchard RJ, et al. 2004. The p75 neurotrophin receptor can induce autophagy and death of cerebellar Purkinje neurons. J. Neurosci. 24:4498-509
111. Zanjani SH, Selimi F, Vogel MW, Haeberle AM, Boeuf J, et al. 2006. Survival of interneurons and parallel fiber synapses in a cerebellar cortex deprived of Purkinje cells: studies in the double mutant mouse Grid2Lc/+;Bax+/+. J. Comp. Neurol. 497:622-35
112. Toth ML, Simon P, Kovacs AL, Vellai T. 2007. Influence of autophagy genes on ion-channel-dependent neuronal degeneration in Caenorhabditis elegans. J. Cell Sci. 120:1134-41
113. Sarkar S, Krishna G, Imarisio S, Saiki S, O'Kane CJ, Rubinsztein DC. 2008. A rational mechanism for combination treatment of Huntington's disease using lithium and rapamycin. Hum. Mol. Genet. 17:170-78
114. Sarkar S, RubinszteinDC. 2008. Small molecule enhancers of autophagy for neurodegenerative diseases. Mol. Biosyst. 4:895-901
115. Lindblad D, Blomenkamp K, Teckman J. 2007. Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. Hepatology 46:1228-35
116. Donohue TM Jr. 2009. Autophagy and ethanol-induced liver injury. World J. Gastroenterol. 15:1178-85
117. He C, Bassik MC, Moresi V, Sun K, Wei Y, et al. 2012. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481:511-15
118. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, et al. 2007. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat. Med. 13:619-24
119. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, et al. 2010. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 6:600-6
120. Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, et al. 2007. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ. Res. 100:914-22
121. Zhao Y, Xue T, Yang X, Zhu H, Ding X, et al. 2010. Autophagy plays an important role in sunitinibmediated cell death in H9c2 cardiac muscle cells. Toxicol. Appl. Pharmacol. 248:20-27
122. Liang XH, Jackson S, SeamanM, Brown K, Kempkes B, et al. 1999. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 402:672-76
123. Massey DC, Parkes M. 2007. Genome-wide association scanning highlights two autophagy genes, ATG16L1 and IRGM, as being significantly associated with Crohn's disease. Autophagy 3:649-51
124. Crighton D, Wilkinson S, O'Prey J, Nelofer S, Smith P, et al. 2006. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 126:121-34
125. Kuo H-P, Lee D-F, Chen C-T, Liu M, Chou C-K, et al. 2010. ARD1 stabilization of TSC2 suppresses tumorigenesis through the mTOR signaling pathway. Sci. Signal. 3:ra9
126. Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, et al. 2006. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 10:51-64
127. Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, et al. 2007. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev. 21:1367-81
128. Kaminskyy VO, Piskunova T, Zborovskaya I, Tchevkina EM, Zhivotovsky B. 2012. Suppression of basal autophagy reduces lung cancer cell proliferation and enhances caspase-dependent and-independent apoptosis by stimulating ROS formation. Autophagy 8(7):1032-44
129. Chen N, Karantza V. 2011. Autophagy as a therapeutic target in cancer. Cancer Biol. Ther. 11:157-68
130. Degtyarev M, De Mazìere A, Orr C, Lin J, Lee BB, et al. 2008. Akt inhibition promotes autophagy and sensitizes PTEN-null tumors to lysosomotropic agents. J. Cell Biol. 183:101-16
131. Amaravadi R, Yu D, Lum J, Bui T, Christophorou M, et al. 2007. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J. Clin. Investig. 117:326-36