Emerging roles for the ubiquitin-proteasome system and autophagy in pancreatic β-cells

American Journal of Physiology - Endocrinology and Metabolism

Volumn 296, Issue 1, 2009, Pages

  Hartley, Taila ^a,b   Brumell, John ^c,d,f   Volchuk, Allen ^a,b,e  

^a UNIVERSITY HEALTH NETWORK   (Canada)

^b Departments of Biochemistry   (Canada)

^c Departments of Molecular Genetics   (Canada)

^d Departments of Physiology   (Canada)

^e UNIVERSITY OF TORONTO   (Canada)

^f Div of Cell Biology   (Canada)

Author keywords

Autophagy; Endoplasmic reticulum stress; Insulin secretion; Ubiquitin proteasome

Indexed keywords

GLUCOSE; INSULIN; PROTEASOME; UBIQUITIN;

AUTOPHAGY; CELL FUNCTION; ENDOPLASMIC RETICULUM STRESS; GLUCOSE BLOOD LEVEL; HUMAN; INSULIN RELEASE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PRIORITY JOURNAL; REVIEW;

ANIMALS; AUTOPHAGY; HUMANS; INSULIN-SECRETING CELLS; PROTEASOME ENDOPEPTIDASE COMPLEX; UBIQUITIN;

EID: 58249108069     PISSN: 01931849     EISSN: 15221555     Source Type: Journal    
DOI: 10.1152/ajpendo.90538.2008     Document Type: Review

References (130)

1. Allaman-Pillet N, Sterling J, Oberson A, Roduit R, Negri S, Sauser C, Nicod P, Beckmann JS, Schorderet DF, Mandrup-Poulsen T, Bonny C. Calcium- and proteasome-dependent degradation of the JNK scaffold protein islet-brain 1. J Biol Chem 278: 48720-48726, 2003.
2. Allen JR, Nguyen LX, Sargent KEG, Lipson KL, Hackett A, Urano F. High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin. Biochem Biophys Res Commun 324: 166-170, 2004.
3. Ashcroft SJ. Glucoreceptor mechanisms and the control of insulin release and biosynthesis. Diabetologia 18: 5-15, 1980.
4. Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292: 1552-1555, 2001.
5. Bernales S, McDonald KL, Walter P. Autophagy counterbalances endoplasmic reticulum expansion during the unfolded protein response. PLoS Biol 4: e423, 2006.
6. Bernales S, Schuck S, Walter P. ER-phagy: selective autophagy of the endoplasmic reticulum. Autophagy 3: 285-287, 2007.
7. Bjorkoy G, Lamark T, Johansen T. p62/SQSTM1: a missing link between protein aggregates and the autophagy machinery. Autophagy 2: 138 -139, 2006.
8. Burks DJ, White MF. IRS proteins and beta-cell function. Diabetes 50: S140-145, 2001.
9. Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC. Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes. Diabetes 53: 1509-1516, 2004.
10. Cao Y, Klionsky DJ. Physiological functions of Atg6/Beclin 1: a unique autophagy-related protein. Cell Res 17: 839-849, 2007.
11. Cardozo AK, Ortis F, Storling J, Feng YM, Rasschaert J, Tonnesen M, van Eylen F, Mandrup-Poulsen T, Herchuelz A, Eizirik DL. Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes 54: 452-461, 2005.
12. Casas S, Gomis R, Gribble FM, Altirriba J, Knuutila S, Novials A. Impairment of the ubiquitin-proteasome pathway is a downstream endoplasmic reticulum stress response induced by extracellular human islet amyloid polypeptide and contributes to pancreatic beta-cell apoptosis. Diabetes 56: 2284-2294, 2007.
13. Castino R, Davies J, Beaucourt S, Isidoro C, Murphy D. Autophagy is a prosurvival mechanism in cells expressing an autosomal dominant familial neurohypophyseal diabetes insipidus mutant vasopressin trans-gene. FASEB J 19: 1021-1023, 2005.
14. Clark A, Edwards CA, Ostle LR, Sutton R, Rothbard JB, Morris JF, Turner RC. Localisation of islet amyloid peptide in lipofuscin bodies and secretory granules of human B-cells and in islets of type-2 diabetic subjects. Cell Tissue Res 257: 179-185, 1989.
15. Cnop M, Ladriere L, Hekerman P, Ortis F, Cardozo AK, Dogusan Z, Flamez D, Boyce M, Yuan J, Eizirik DL. Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. J Biol Chem 282: 3989 - 3997, 2007.
16. Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54, Suppl 2: S97-S107, 2005.
17. Codogno P, Meijer AJ. Autophagy and signaling: their role in cell survival and cell death. Cell Death Differ 12, Suppl 2: 1509-1518, 2005.
18. Corboy MJ, Thomas PJ, Wigley WC. Aggresome formation. Methods Mol Biol 301: 305-327, 2005.
19. Coux O, Tanaka K, Goldberg AL. Structure and functions of the 20S and 26S proteasomes. Annu Rev Biochem 65: 801-847, 1996.
20. Demuro A, Mina E, Kayed R, Milton SC, Parker I, Glabe CG. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280: 17294-17300, 2005.
21. Ding WX, Ni HM, Gao W, Yoshimori T, Stolz D, Ron D, Yin XM. Linking of autophagy to ubiquitin-proteasome system is important for the regulation of endoplasmic reticulum stress and cell viability. Am J Pathol 171: 513-524, 2007.
22. Ding WX, Yin XM. Sorting, recognition and activation of the misfolded protein degradation pathways through macroautophagy and the proteasome. Autophagy 4: 141-150, 2008.
23. Dodson G, Steiner D. The role of assembly in insulin's biosynthesis. Curr Opin Struct Biol 8: 189-194, 1998.
24. Drucker DJ. The role of gut hormones in glucose homeostasis. J Clin Invest 117: 24-32, 2007.
25. Eizirik DL, Cardozo AK, Cnop M. The role of endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29: 42-61, 2008.
26. Eizirik DL, Mandrup-Poulsen T. A choice of death-the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia 44: 2115-2133, 2001.
27. Eskelinen EL, Illert AL, Tanaka Y, Schwarzmann G, Blanz J, Von Figura K, Saftig P. Role of LAMP-2 in lysosome biogenesis and autophagy. Mol Biol Cell 13: 3355-3368, 2002.
28. Fang S, Lorick KL, Jensen JP, Weissman AM. RING finger ubiqutin protein ligases: implications for tumorigenesis, metastasis and for molecular targets in cancer. Semin Cancer Biol 13: 5-14, 2003.
29. Fonseca SG, Lipson KL, Urano F. Endoplasmic reticulum stress signaling in pancreatic beta-cells. Antioxid Redox Signal 9: 2335-2344, 2007.
30. Fortun J, Dunn, WA Jr, Joy S, Li J, Notterpek L. Emerging role for autophagy in the removal of aggresomes in Schwann cells. J Neurosci 23: 10672-10680, 2003.
31. Fujita E, Kouroku Y, Isoai A, Kumagai H, Misutani A, Matsuda C, Hayashi YK, Momoi T. Two endoplasmic reticulum-associated degradation (ERAD) systems for the novel variant of the mutant dysferlin: ubiquitin/proteasome ERAD (I) and autophagy/lysosome ERAD (II). Hum Mol Genet 16: 618 -629, 2007.
32. Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19: 2092-2100, 2008.
33. Gomez-Martin D, Diaz-Zamudio M, Alcocer-Varela J. Ubiquitination system and autoimmunity: the bridge towards the modulation of the immune response. Autoimmun Rev 7: 284-290, 2008.
34. Grankvist K, Marklund SL, Taljedal IB. CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 199: 393-398, 1981.
35. Halban PA. Structural domains and molecular lifestyles of insulin and its precursors in the pancreatic beta cell. Diabetologia 34: 767-778, 1991.
36. Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, Inagaki F, Ohsumi Y. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 282: 37298 - 37302, 2007.
37. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, Yokoyama M, Mishima K, Saito I, Okano H, Mizushima N. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 441: 885-889, 2006.
38. Hara T, Takamura A, Kishi C, Iemura S, Natsume T, Guan JL, Mizushima N. FIP200, a ULK-interacting protein, is required for auto-phagosome formation in mammalian cells. J Cell Biol 181: 497-510, 2008.
39. Hatakeyama S, Natayama KI. U-box proteins as a new family of ubiquitin ligases. Biochem Biophys Res Commun 302: 635-645, 2003.
40. Hayden MR, Tyagi SC, Kerklo MM, Nicolls MR. Type 2 diabetes mellitus as a conformational disease. JOP 6: 287-302, 2005.
41. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 67: 425-479, 1998.
42. Hidvegi T, Schmidt BZ, Hale P, Perlmutter DH. Accumulation of mutant alpha 1-antitrypsin Z in the endoplasmic reticulum activates caspases-4 and -12, NFkappaB, and BAP31 but not the unfolded protein response. J Biol Chem 280: 39002-39015, 2005.
43. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860-867, 2006.
44. Hoyer-Hansen M, Jaattela M. Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14: 1576-1582, 2007.
45. Huang CJ, Haataja L, Gurlo T, Butler AE, Wu X, Soeller WC, Butler P. Induction of endoplasmic reticulum stress-induced β-cell apoptosis and accumulation of polyubiquitinated proteins by human islet amyloid polypeptide. Am J Physiol Endocrinol Metab 293: E1656- E1662, 2007.
46. Hull RL, Westermark GT, Westermark P, Kahn SE. Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes. J Clin Endocrinol Metab 89: 3629-3643, 2004.
47. Ichimura Y, Kirisako T, Takao T, Satomi Y, Shimonishi Y, Ishihara N, Mizushima N, Tanida I, Kominami E, Ohsumi M, Noda T, Ohsumi Y. A ubiquitin-like system mediates protein lipidation. Nature 408: 488-492, 2000.
48. Itoh T, Fujita N, Kanno E, Yamamoto A, Yoshimori T, Fukuda M. Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. Mol Biol Cell 19: 2916 -2925, 2008.
49. Janson J, Ashley RH, Harrison D, McIntyre S, Butler PS. The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes 48: 491-498, 1999.
50. Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC. Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci USA 93: 7283-7288, 1996.
51. Johnson KH, O'Brien TD, Hayden DW, Jordan K, Ghobrial HK, Mahoney WC, Westermark P. Immunolocalization of islet amyloid polypeptide (IAPP) in pancreatic beta cells by means of peroxidase-antiperoxidase (PAP) and protein-A-gold techniques. Am J Pathol 130: 1-8, 1988.
52. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, Kominami E, Ohsumi M, Yoshimori T. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J 19: 5720-5728, 2000.
53. Kaniuk NA, Kiraly M, Bates H, Vranic M, Volchuk A, Brumell JH. Ubiquitinated-protein aggregates form in pancreatic beta-cells during diabetes-induced oxidative stress and are regulated by autophagy. Diabetes 56: 930-939, 2007.
54. Karaskov E, Scott C, Zhang L, Teodoro T, Ravazzola M, Volchuk A. Chronic palmitate but not oleate exposure induces endoplasmic reticulum stress, which may contribute to INS-1 pancreatic beta-cell apoptosis. Endocrinology 147: 3398-3407, 2006.
55. Kawaguchi M, Minami K, Nagashima K, Seino S. Essential role of ubiquitin-proteasome system in normal regulation of insulin secretion. J Biol Chem 281: 13015-13020, 2006.
56. Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M, Eizirik DL. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology 145: 5087-5096, 2004.
57. Kincaid MM, Cooper AA. ERADicate ER stress or die trying. Antioxid Redox Signal 9: 2373-2387, 2007.
58. Kitiphongspattana K, Mathews CE, Leiter EH, Gaskins HR. Proteasome inhibition alters glucose-stimulated (pro)insulin secretion and turnover in pancreatic beta-cells. J Biol Chem 280: 15727-15734, 2005.
59. Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 8: 931-937, 2007.
60. Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, Ueno T, Koike M, Uchiyama Y, Kominami E, Tanaka K. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 441: 880-884, 2006.
61. Komatsu M, Waguri S, Koike M, Sou YS, Ueno T, Hara T, Mizushima N, Iwata J, Ezaki J, Murata S, Hamazaki J, Nishito Y, Iemura S, Natsume T, Yanagawa T, Uwayama J, Warabi E, Yoshida H, Ishii T, Kobayashi A, Yamamoto M, Yue Z, Uchiyama Y, Komi-nami E, Tanaka K. Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131: 1149-1163, 2007.
62. Kopito RR. Aggresomes, inclusion bodies and protein aggregation. Trends Cell Biol 10: 524-530, 2000.
63. Kouroku Y, Fujita E, Tanida I, Ueno T, Isoai A, Kumagai H, Ogawa S, Kaufman RJ, Kominami E, Momoi T. ER stress (PERK/eIf2alpha phosphorylation) mediates the polyglutamine-induced LC3 conversion, an essential step for autophagy formation. Cell Death Differ 14: 230239, 2007.
64. Kwon G, Corbett JA, Hauser S, Hill JR, Turk J, McDaniel ML. Evidence for involvement of the proteasome complex (26S) and NFkB in
65. IL-1beta-induced nitric oxide and prostaglandin production by rat islets and RINm5F cells. Diabetes 47: 583-591, 1998.
66. Lackner C, Dlaska D, Fuchsbichler A, Stumptner C, Gogg-Kamerer M, Zatloukal K, Denk H. p62 protein is expressed in pancreatic beta cells. J Pathol 206: 402-408, 2005.
67. Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ. Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50: 752-763, 2007.
68. Lelouard H, Ferrand V, Marquet D, Bania J, Camosseto V, David A, Gatti E, Pierre P. Dendritic cell aggresome-like induced structures are dedicated areas for ubiquitination and storage of newly synthesized defective proteins. J Cell Biol 164: 667-675, 2004.
69. Lenzen S, Drinkgern J, Tiedge M. Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20: 463-466, 1996.
70. Levine B, Klionsky DJ. Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6: 463477, 2004.
71. Li C, Capan E, Zhao J, Stolz D, Watkins SC, Jin S, Lu B. Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. J Immunol 177: 5163-5168, 2006.
72. Lopez-Avalos MD, Duvivier-Kali VF, Xu G, Bonner-Weir S, Sharma A, Weir GC. Evidence for a role of the ubiquitin-proteasome pathway in pancreatic islets. Diabetes 55: 1223-1231, 2006.
73. Lorenzo A, Razzaboni B, Weir GC, Yankner BA. Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus. Nature 368: 756-760, 1994.
74. Lukinius A, Wilander E, Westermark GT, Engstrom U, Westermark P. Co-localization of islet amyloid polypeptide and insulin in the B-cell secretory granules of the human pancreatic islets. Diabetologia 32: 240-244, 1989.
75. Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P. Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that beta-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes 51: 1437-1442, 2002.
76. Marsh BJ, Soden C, Alarcon C, Wicksteed BL, Yaekura K, Costin AJ, Morgan GP, Rhodes CJ. Regulated autophagy controls hormone content in secretory-deficient pancreatic endocrine beta-cells. Mol Endocrinol 21: 2255-2269, 2007.
77. McClellan AJ, Tam S, Kaganovich D, Frydman J. Protein quality control: chaperones culling corrupt conformations. Nat Cell Biol 7: 736-741, 2005.
78. Meier JJ, Kayed R, Lin CY, Gurlo T, Haataja L, Jayasinghe S, Langen R, Glabe CG, Butler PC. Inhibition of human IAPP fibril formation does not prevent beta-cell death: evidence for distinct actions of oligomers and fibrils of human IAPP. Am J Physiol Endocrinol Metab 291: E1317-E1324, 2006.
79. Meijer AJ, Codogno P. Macroautophagy: protector in the diabetes drama? Autophagy 3: 523-526, 2007.
80. Melloul D, Marshak S, Cerasi E. Regulation of insulin gene transcription. Diabetologia 45: 309-326, 2002.
81. Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol 7: 766-772, 2005.
82. Minami K, Yano H, Miki T, Nagashima K, Wang CZ, Tanaka H, Miyazaki JI, Seino S. Insulin secretion and differential gene expression in glucose-responsive and -unresponsive MIN6 sublines. Am J Physiol Endocrinol Metab 279: E773-E781, 2000.
83. Mirzabekov TA, Lin MC, Kagan BL. Pore formation by the cytotoxic islet amyloid peptide amylin. J Biol Chem 271: 1988-1992, 1996.
84. Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 4: 192-201, 2003.
85. Nakatogawa H, Ichimura Y, Ohsumi Y. Atg8, a ubiquitin-like protein required for autophagosome formation, mediates membrane tethering and hemifusion. Cell 130: 165-178, 2007.
86. Nakayama KI, Nakayama K. Ubiquitin ligases: cell-cycle control and cancer. Nat Rev Cancer 6: 369-381, 2006.
87. Nishino I, Fu J, Tanji K, Yamada T, Shimojo S, Koori T, Mora M, Riggs JE, Oh SJ, Koga Y, Sue CM, Yamamoto A, Murakami N, Shanske S, Byrne E, Bonilla E, Nonaka I, DiMauro S, Hirano M. Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease). Nature 406: 906-910, 2000.
88. Noda T, Fujita N, Yoshimori T. The Ubi brothers reunited. Autophagy 4: 540-541, 2008.
89. Nolan CJ, Madiraju MS, Delghingaro-Augusto V, Peyot ML, Prentki M. Fatty acid signaling in the beta-cell and insulin secretion. Diabetes 55: S16-S23, 2006.
90. Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarbak J, Urano F, Imaizumi K. Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26: 9220 - 9231, 2006.
91. Onodera J, Ohsumi Y. Ald6p is a preferred target for autophagy in yeast, Saccharomyces cerevisiae. J Biol Chem 279: 16071-16076, 2004.
92. Orci L, Ravazzola M, Amherdt M, Yanaihara C, Yanaihara N, Halban P, Renold AE, Perrelet A. Insulin, not C-peptide (proinsulin), is present in crinophagic bodies of the pancreatic B-cell. J Cell Biol 98: 222-228, 1984.
93. Oyadomari S, Araki E, Mori M. Endoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells. Apoptosis 7: 335-345, 2002.
94. Perlmutter DH. The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. Autophagy 2: 258 -263, 2006.
95. Qing G, Yan P, Qu Z, Liu H, Xiao G. Hsp90 regulates processing of NF-kappaB2 p100 involving protection of NF-kappaB-inducing kinase (NIK) from autophagy-mediated degradation. Cell Res 17: 520-530, 2007.
96. Qing G, Yan P, Xiao G. Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK). Cell Res 16: 895-901, 2006.
97. Reggiori F. Membrane origin for autophagy. Curr Top Dev Biol 74: 1-30, 2006.
98. Ren J, Jin P, Wang E, Liu E, Harlan DM, Li X, Stroncek DF. Pancreatic islet therapy for type 1 diabetes: understanding the effects of glucose stimulation on islets in order to produce better islets for transplantation. J Transl Med 5: 1, 2007.
99. Rhodes CJ. Processing the insulin molecule. In: Diabetes Mellitus: A Fundamental and Clinical Text (3rd ed.), edited by LeRoith D, Taylor SI, and Olefsky JM. Philadelphia, PA: Lippincott-Raven, 2004, p. 27-50.
100. Robertson RP. Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem 279: 42351-42354, 2004.
101. Robertson RP, Harmon JS. Diabetes, glucose toxicity, and oxidative stress: a case of double jeopardy for the pancreatic islet beta cell. Free Radic Biol Med 41: 177-184, 2006.
102. Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8: 519-529, 2007.
103. Rorsman P, Renstrom E. Insulin granule dynamics in pancreatic beta cells. Diabetologia 46: 1029-1045, 2003.
104. Rui L, Fisher TL, Thomas J, White MF. Regulation of insulin/insulinlike growth factor-1 signaling by proteasome-mediated degradation of insulin receptor substrate-2. J Biol Chem 276: 40362-40367, 2001.
105. Rutkowski DT, Kaufman RJ. All roads lead to ATF4. Dev Cell 4: 442-444, 2003.
106. Scheffner M, Staub O. HECT E3s and human disease. BMC Biochem 8, Suppl 1: S6, 2007.
107. Schnell Landstrom AH, Andersson A, Borg LAH. Lysosomes and pancreatic islet function: adaptation of beta-cell lysosomes to various metabolic demands. Metabolism 40: 399 -405, 1991.
108. Schuit FC, In't Veld PA, Pipeleers DG. Glucose stimulates proinsulin biosynthesis by a dose-dependent recruitment of pancreatic beta cells. Proc Natl Acad Sci USA 85: 3865-3869, 1988.
109. Sitia R, Molteni SN. Stress, protein (mis)folding, and signaling: the redox connection. Sci STKE 2004: pe27, 2004.
110. Subramani S, Farre JC. A ubiquitin-like protein involved in membrane fusion. Cell 130: 18-20, 2007.
111. Szeto J, Kaniuk NA, Canadien V, Nisman R, Mizushima N, Yoshimori T, Bazett-Jones DP, Brumell JH. ALIS are stress-induced protein storage compartments for substrates of the proteasome and autophagy. Autophagy 2: 189 -199, 2006.
112. Tan JM, Wong ES, Dawson VL, Dawson TM, Lim KL. Lysine 63-linked polyubiquitin potentially partners with p62 to promote the clearance of protein inclusions by autophagy. Autophagy 4: 251-253, 2008.
113. Taniguchi CM, Emanuelli B, Kahn CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7: 85-96, 2006.
114. Twig G, Elorza A, Molina AJA, Mohamed H, Wikstrom JD, Walzer G, Stiles L, Haigh SE, Katz S, Las G, Alroy J, Wu M, Py BF, Yuan J, Deeney JT, Corkey BE, Shirihai OS. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J 27: 433-446, 2008.
115. Uchizono Y, Alarcon C, Wicksteed BL, Marsh BJ, Rhodes CJ. The balance between proinsulin biosynthesis and insulin secretion: where can imbalance lead? Diabetes Obes Metab 9, Suppl 2: 56-66, 2007.
116. Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D. Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287: 664-666, 2000.
117. Vaulont S, Vasseur-Cognet M, Kahn A. Glucose regulation of gene transcription. J Biol Chem 275: 31555-31558, 2000.
118. Wang H, Kouri G, Wollheim CB. ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. J Cell Sci 118: 3905-3915, 2005.
119. Welchman RL, Gordon C, Mayer RJ. Ubiquitin and ubiquitin-like proteins as multifunctional signals. Nat Rev Mol Cell Biol 6: 599 -609, 2005.
120. Welsh N, Margulis B, Borg LA, Wiklund HJ, Saldeen J, Flodstrom M, Mello MA, Andersson A, Pipeleers DG, Hellerstrom C, Eizirik DL. Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med 1: 806-820, 1995.
121. Westermark P, Wilander E, Westermark GT, Johnson KH. Islet amyloid polypeptide-like immunoreactivity in the islet B cells of type 2
122. (non-insulin-dependent) diabetic and non-diabetic individuals. Diabetologia 30: 887-892, 1987.
123. Wicksteed B, Alarcon C, Briaud I, Lingohr MK, Rhodes CJ. Glucose-induced translational control of proinsulin biosynthesis is proportional to preproinsulin mRNA levels in islet beta-cells but not regulated via a positive feedback of secreted insulin. J Biol Chem 278: 420804-2090, 2003.
124. Wicksteed B, Uchizono Y, Alarcon C, McCuaig JF, Shalev A, Rhodes CJ. A cis-element in the 5' untranslated region of the preproinsulin mRNA (ppIGE) is required for glucose regulation of proinsulin translation. Cell Metab 5: 221-227, 2007.
125. Wiseman RL, Balch WE. A new pharmacology-drugging stressed folding pathways. Trends Mol Med 11: 347-350, 2005.
126. Yan FF, Lin CW, Cartier EA, Shyng SL. Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of β-cell ATP-sensitive potassium channels. Am J Physiol Cell Physiol 289: C1351-C1359, 2005.
127. Yorimitsu T, Nair U, Yang Z, Klionsky DJ. Endoplasmic reticulum stress triggers autophagy. J Biol Chem 281: 30299-30304, 2006.
128. Yu L, Alva A, Su H, Dutt P, Freundt E, Welsh S, Baehrecke EH, Lenardo MJ. Regulation of an ATG7-beclin 1 program of autophagic cell death by caspase-8. Science 304: 1500-1502, 2004.
129. Yusta B, Baggio LL, Estall JL, Koehler JA, Holland DP, Li H, Pipeleers D, Ling Z, Drucker DJ. GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metab 4: 391-406, 2006.
130. Zhong L, Georgia S, Tschen SI, Nakayama K, Nakayama K, Bhushan A. Essential role of Skp2-mediated p27 degradation in growth and adaptive expansion of pancreatic beta cells. J Clin Invest 117: 2869 -2876, 2007.