PRAS40 Is an Integral Regulatory Component of Erythropoietin mTOR Signaling and Cytoprotection

PLoS ONE

Volumn 7, Issue 9, 2012, Pages

  Chong, Zhao Zhong ^a,c   Shang, Yan Chen ^a,c   Wang, Shaohui ^a,c   Maiese, Kenneth ^a,b,c  

^a Laboratory of Cellular and Molecular Signaling   (United States)

^b RUTGERS CANCER INSTITUTE OF NEW JERSEY   (United States)

^c New Jersey Health Sciences University   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CASPASE 3; DOCKING PROTEIN; ERYTHROPOIETIN; GLUCOSE; INITIATION FACTOR 4E BINDING PROTEIN 1; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; OXYGEN; PHOSPHATIDYLINOSITOL 3 KINASE; PRAS40 PROTEIN; PROLINE; PROTEIN; PROTEIN KINASE B; S6 KINASE; STAT5 PROTEIN; UNCLASSIFIED DRUG;

APOPTOSIS; ARTICLE; CELL DAMAGE; CELL PROTECTION; CELL SURVIVAL; ENZYME ACTIVATION; GENE SILENCING; HUMAN; HUMAN CELL; NEUROLOGIC DISEASE; OXIDATIVE STRESS; PROTEIN PHOSPHORYLATION; PROTEIN PROCESSING;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; APOPTOSIS; CASPASE 3; CELL LINE, TUMOR; CELL SURVIVAL; CYTOPROTECTION; DNA; ENZYME ACTIVATION; ERYTHROPOIETIN; GENOME, HUMAN; HUMANS; MAP KINASE SIGNALING SYSTEM; PHOSPHATIDYLINOSITOL 3-KINASES; PHOSPHOPROTEINS; PHOSPHORYLATION; PROTO-ONCOGENE PROTEINS C-AKT; RIBOSOMAL PROTEIN S6 KINASES, 70-KDA; SIGNAL TRANSDUCTION; STAT5 TRANSCRIPTION FACTOR; TOR SERINE-THREONINE KINASES;

EUKARYOTA; MAMMALIA;

EID: 84866479521     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0045456     Document Type: Article

References (127)

1. Bajda M, Guzior N, Ignasik M, Malawska B, (2011) Multi-target-directed ligands in Alzheimer's disease treatment. Curr Med Chem 18: 4949-4975.
2. Enz R, (2012) Metabotropic glutamate receptors and interacting proteins: evolving drug targets. Curr Drug Targets 13: 145-156.
3. Maiese K, Chong ZZ, Hou J, Shang YC, (2009) New strategies for Alzheimer's disease and cognitive impairment. Oxid Med Cell Longev 2: 279-289.
4. Chong ZZ, Li F, Maiese K, (2005) Oxidative stress in the brain: Novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75: 207-246.
5. Srivastava S, Haigis MC, (2011) Role of sirtuins and calorie restriction in neuroprotection: implications in Alzheimer's and Parkinson's diseases. Curr Pharm Des 17: 3418-3433.
6. Zhang G, Zhao Z, Gao L, Deng J, Wang B, et al. (2011) Gypenoside attenuates white matter lesions induced by chronic cerebral hypoperfusion in rats. Pharmacol Biochem Behav 99: 42-51.
7. Chong ZZ, Shang YC, Wang S, Maiese K, (2012) SIRT1: New avenues of discovery for disorders of oxidative stress. Expert Opin Ther Targets 16: 167-178.
8. Shacka JJ, Roth KA, Zhang J, (2008) The autophagy-lysosomal degradation pathway: role in neurodegenerative disease and therapy. Front Biosci 13: 718-736.
9. Kashihara N, Haruna Y, Kondeti VK, Kanwar YS, (2010) Oxidative stress in diabetic nephropathy. Curr Med Chem 17: 4256-4269.
10. Maiese K, Chong ZZ, Shang YC, Hou J, (2011) Novel Avenues of Drug Discovery and Biomarkers for Diabetes Mellitus. J Clin Pharmacol 51: 128-152.
11. Yang H, Jin X, Kei Lam CW, Yan SK, (2011) Oxidative stress and diabetes mellitus. Clin Chem Lab Med 49: 1773-1782.
12. Kumral A, Tuzun F, Oner MG, Genc S, Duman N, et al. (2011) Erythropoietin in neonatal brain protection: the past, the present and the future. Brain Dev 33: 632-643.
13. Maiese K, Chong ZZ, Li F, Shang YC, (2008) Erythropoietin: elucidating new cellular targets that broaden therapeutic strategies. Prog Neurobiol 85: 194-213.
14. Chong ZZ, Li F, Maiese K, (2005) Erythropoietin requires NF-kappaB and its nuclear translocation to prevent early and late apoptotic neuronal injury during beta-amyloid toxicity. Curr Neurovasc Res 2: 387-399.
15. Chong ZZ, Lin SH, Kang JQ, Maiese K, (2003) Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8. J Neurosci Res 71: 659-669.
16. Digicaylioglu M, Lipton SA, (2001) Erythropoietin-mediated neuroprotection involves cross-talk between Jak2 and NF-kappaB signalling cascades. Nature 412: 641-647.
17. Park KH, Choi NY, Koh SH, Park HH, Kim YS, et al. (2011) L-DOPA neurotoxicity is prevented by neuroprotective effects of erythropoietin. Neurotoxicology 32: 879-887.
18. Ruscher K, Freyer D, Karsch M, Isaev N, Megow D, et al. (2002) Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci 22: 10291-10301.
19. Simon F, Scheuerle A, Groger M, Vcelar B, McCook O, et al. (2011) Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. Intensive Care Med 37: 1525-1533.
20. Velly L, Pellegrini L, Guillet B, Bruder N, Pisano P, (2010) Erythropoietin 2nd cerebral protection after acute injuries: a double-edged sword? Pharmacol Ther 128: 445-459.
21. Chong ZZ, Hou J, Shang YC, Wang S, Maiese K, (2011) EPO Relies upon Novel Signaling of Wnt1 that Requires Akt1, FoxO3a, GSK-3beta, and beta-Catenin to Foster Vascular Integrity During Experimental Diabetes. Curr Neurovasc Res 8: 103-120.
22. Chong ZZ, Kang JQ, Maiese K, (2002) Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases. Circulation 106: 2973-2979.
23. Xu Y, Tian Y, Wei HJ, Chen J, Dong JF, et al. (2011) Erythropoietin increases circulating endothelial progenitor cells and reduces the formation and progression of cerebral aneurysm in rats. Neuroscience 181: 292-299.
24. Yamada M, Burke C, Colditz P, Johnson DW, Gobe GC, (2011) Erythropoietin protects against apoptosis and increases expression of non-neuronal cell markers in the hypoxia-injured developing brain. J Pathol 224: 101-109.
25. Hamed S, Egozi D, Kruchevsky D, Teot L, Gilhar A, et al. (2010) Erythropoietin improves the survival of fat tissue after its transplantation in nude mice. PLoS ONE 5: e13986.
26. Loeliger MM, Mackintosh A, De Matteo R, Harding R, Rees SM, (2011) Erythropoietin protects the developing retina in an ovine model of endotoxin-induced retinal injury. Invest Ophthalmol Vis Sci 52: 2656-2661.
27. Shang YC, Chong ZZ, Wang S, Maiese K, (2011) Erythropoietin and Wnt1 Govern Pathways of mTOR, Apaf-1, and XIAP in Inflammatory Microglia. Curr Neurovasc Res 8: 270-285.
28. Solling C (2011) Organ-Protective and Immunomodulatory Effects of Erythropoietin - An Update on Recent Clinical Trials. Basic Clin Pharmacol Toxicol.
29. Chong ZZ, Maiese K, (2007) Erythropoietin involves the phosphatidylinositol 3-kinase pathway, 14-3-3 protein and FOXO3a nuclear trafficking to preserve endothelial cell integrity. Br J Pharmacol 150: 839-850.
30. Hou J, Wang S, Shang YC, Chong ZZ, Maiese K, (2011) Erythropoietin Employs Cell Longevity Pathways of SIRT1 to Foster Endothelial Vascular Integrity During Oxidant Stress. Curr Neurovasc Res 8: 220-235.
31. Su KH, Shyue SK, Kou YR, Ching LC, Chiang AN, et al. (2011) beta Common receptor integrates the erythropoietin signaling in activation of endothelial nitric oxide synthase. J Cell Physiol 226: 3330-3339.
32. Takeyama T, Takemura G, Kanamori H, Kawaguchi T, Ogino A, et al. (2012) Asialoerythropoietin, a nonerythropoietic derivative of erythropoietin, displays broad anti-heart failure activity. Circ Heart Fail 5: 274-285.
33. Shang YC, Chong ZZ, Wang S, Maiese K, (2012) Prevention of beta-amyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL. Aging (Albany NY) 4: 187-201.
34. Kim J, Jung Y, Sun H, Joseph J, Mishra A, et al. (2012) Erythropoietin mediated bone formation is regulated by mTOR signaling. J Cell Biochem 113: 220-228.
35. Choi KC, Kim SH, Ha JY, Kim ST, Son JH, (2010) A novel mTOR activating protein protects dopamine neurons against oxidative stress by repressing autophagy related cell death. J Neurochem 112: 366-376.
36. Chen L, Xu B, Liu L, Luo Y, Yin J, et al. (2010) Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells. Lab Invest 90: 762-773.
37. Chong ZZ, Li F, Maiese K, (2007) The pro-survival pathways of mTOR and protein kinase B target glycogen synthase kinase-3beta and nuclear factor-kappaB to foster endogenous microglial cell protection. Int J Mol Med 19: 263-272.
38. Sancak Y, Thoreen CC, Peterson TR, Lindquist RA, Kang SA, et al. (2007) PRAS40 is an insulin-regulated inhibitor of the mTORC1 protein kinase. Mol Cell 25: 903-915.
39. Wang H, Zhang Q, Wen Q, Zheng Y, Philip L, et al. (2012) Proline-rich Akt substrate of 40kDa (PRAS40): a novel downstream target of PI3k/Akt signaling pathway. Cell Signal 24: 17-24.
40. Wang L, Harris TE, Roth RA, Lawrence JC, (2007) PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 282: 20036-20044.
41. Chong ZZ, Maiese K, (2012) Mammalian Target of Rapamycin Signaling in Diabetic Cardiovascular Disease. Cardiovasc Diabetol 11: 45.
42. Das F, Dey N, Venkatesan B, Kasinath BS, Ghosh-Choudhury N, et al. (2011) High glucose upregulation of early-onset Parkinson's disease protein DJ-1 integrates the PRAS40/TORC1 axis to mesangial cell hypertrophy. Cell Signal 23: 1311-1319.
43. Kapoor V, Zaharieva MM, Das SN, Berger MR, (2012) Erufosine simultaneously induces apoptosis and autophagy by modulating the Akt-mTOR signaling pathway in oral squamous cell carcinoma. Cancer Lett 319: 39-48.
44. Wang J, Xiao X, Zhang Y, Shi D, Chen W, et al. (2012) Simultaneous modulation of COX-2, p300, Akt, and Apaf-1 signaling by melatonin to inhibit proliferation and induce apoptosis in breast cancer cells. J Pineal Res.
45. Furuichi T, Liu W, Shi H, Miyake M, Liu KJ, (2005) Generation of hydrogen peroxide during brief oxygen-glucose deprivation induces preconditioning neuronal protection in primary cultured neurons. J Neurosci Res 79: 816-824.
46. Weih M, Schmitt M, Gieche J, Harms C, Ruscher K, et al. (2001) Proteolysis of oxidized proteins after oxygen-glucose deprivation in rat cortical neurons is mediated by the proteasome. J Cereb Blood Flow Metab 21: 1090-1096.
47. Balan V, Miller GS, Kaplun L, Balan K, Chong ZZ, et al. (2008) Life span extension and neuronal cell protection by Drosophila nicotinamidase. J Biol Chem 283: 27810-27819.
48. Chong ZZ, Li F, Maiese K, (2007) Cellular demise and inflammatory microglial activation during beta-amyloid toxicity are governed by Wnt1 and canonical signaling pathways. Cell Signal 19: 1150-1162.
49. Chong ZZ, Shang YC, Hou J, Maiese K, (2010) Wnt1 neuroprotection translates into improved neurological function during oxidant stress and cerebral ischemia through AKT1 and mitochondrial apoptotic pathways. Oxid Med Cell Longev 3: 153-165.
50. Chong ZZ, Kang JQ, Maiese K, (2003) Apaf-1, Bcl-xL, Cytochrome c, and Caspase-9 Form the Critical Elements for Cerebral Vascular Protection by Erythropoietin. J Cereb Blood Flow Metab 23: 320-330.
51. Shang YC, Chong ZZ, Hou J, Maiese K, (2009) The forkhead transcription factor FoxO3a controls microglial inflammatory activation and eventual apoptotic injury through caspase 3. Curr Neurovasc Res 6: 20-31.
52. Chong ZZ, Kang JQ, Maiese K, (2003) Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways. Br J Pharmacol 138: 1107-1118.
53. Chong ZZ, Shang YC, Zhang L, Wang S, Maiese K, (2010) Mammalian target of rapamycin: hitting the bull's-eye for neurological disorders. Oxid Med Cell Longev 3: 374-391.
54. Reynolds THt, Bodine SC, Lawrence JC Jr, (2002) Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem 277: 17657-17662.
55. Chiang GG, Abraham RT, (2005) Phosphorylation of mammalian target of rapamycin (mTOR) at Ser-2448 is mediated by p70S6 kinase. J Biol Chem 280: 25485-25490.
56. Pearson RB, Dennis PB, Han JW, Williamson NA, Kozma SC, et al. (1995) The principal target of rapamycin-induced p70s6k inactivation is a novel phosphorylation site within a conserved hydrophobic domain. Embo J 14: 5279-5287.
57. Magagnin MG, van den Beucken T, Sergeant K, Lambin P, Koritzinsky M, et al. (2008) The mTOR target 4E-BP1 contributes to differential protein expression during normoxia and hypoxia through changes in mRNA translation efficiency. Proteomics 8: 1019-1028.
58. Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N, (1998) 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 12: 502-513.
59. Bhandari BK, Feliers D, Duraisamy S, Stewart JL, Gingras AC, et al. (2001) Insulin regulation of protein translation repressor 4E-BP1, an eIF4E-binding protein, in renal epithelial cells. Kidney Int 59: 866-875.
60. Sato A, Sunayama J, Matsuda K, Tachibana K, Sakurada K, et al. (2010) Regulation of neural stem/progenitor cell maintenance by PI3K and mTOR. Neurosci Lett 470: 115-120.
61. Wymann MP, Bulgarelli-Leva G, Zvelebil MJ, Pirola L, Vanhaesebroeck B, et al. (1996) Wortmannin inactivates phosphoinositide 3-kinase by covalent modification of Lys-802, a residue involved in the phosphate transfer reaction. Mol Cell Biol 16: 1722-1733.
62. Vlahos CJ, Matter WF, Hui KY, Brown RF, (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269: 5241-5248.
63. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, et al. (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278: 10189-10194.
64. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH, (2007) Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 9: 316-323.
65. Ammar HI, Saba S, Ammar RI, Elsayed LA, Ghaly WB, et al. (2011) Erythropoietin protects against doxorubicin-induced heart failure. Am J Physiol Heart Circ Physiol 301: H2413-2421.
66. Canadillas S, Ortega R, Estepa JC, Egea J, Gonzalez-Menchen A, et al. (2010) Darbepoetin-alpha treatment enhances glomerular regenerative process in the Thy-1 glomerulonephritis model. Am J Physiol Renal Physiol 299: F1278-1287.
67. Wang Y, Hu X, Xie X, He A, Liu X, et al. (2011) Effects of mesenchymal stem cells on matrix metalloproteinase synthesis in cardiac fibroblasts. Exp Biol Med (Maywood) 236: 1197-1204.
68. Xie Z, Chen F, Wu X, Zhuang C, Zhu J, et al. (2012) Effects of supplemental erythropoietin on its receptor expression and signal transduction pathways in rat model of retinal detachment. Curr Eye Res 37: 138-144.
69. Ji YQ, Zhang YQ, Li MQ, Du MR, Wei WW, et al. (2011) EPO improves the proliferation and inhibits apoptosis of trophoblast and decidual stromal cells through activating STAT-5 and inactivating p38 signal in human early pregnancy. Int J Clin Exp Pathol 4: 765-774.
70. Muller J, Sperl B, Reindl W, Kiessling A, Berg T, (2008) Discovery of chromone-based inhibitors of the transcription factor STAT5. Chembiochem 9: 723-727.
71. Hancock CN, Macias A, Lee EK, Yu SY, Mackerell AD, et al. (2005) Identification of novel extracellular signal-regulated kinase docking domain inhibitors. J Med Chem 48: 4586-4595.
72. Caprara C, Grimm C, (2012) From oxygen to erythropoietin: relevance of hypoxia for retinal development, health and disease. Prog Retin Eye Res 31: 89-119.
73. Holopainen IE, Lauren HB, (2012) Glutamate signaling in the pathophysiology and therapy of prenatal insults. Pharmacol Biochem Behav 100: 825-834.
74. Maiese K, Chong ZZ, Shang YC, Wang S, (2011) Translating cell survival and cell longevity into treatment strategies with SIRT1. Rom J Morphol Embryol 52: 1173-1185.
75. Singh N, Sharma G, Mishra V, Raghubir R (2012) Hypoxia Inducible Factor-1: Its Potential Role In Cerebral Ischemia. Cell Mol Neurobiol.
76. Uzbay TI, (2012) The pharmacological importance of agmatine in the brain. Neurosci Biobehav Rev 36: 502-519.
77. Ullah N, Lee HY, Naseer MI, Ullah I, Suh JW, et al. (2011) Nicotinamide inhibits alkylating agent-induced apoptotic neurodegeneration in the developing rat brain. PLoS ONE 6: e27093.
78. Ullah N, Ullah I, Lee HY, Naseer MI, Seok PM, et al. (2012) Protective Function of Nicotinamide Against Ketamine-induced Apoptotic Neurodegeneration in the Infant Rat Brain. J Mol Neurosci 47: 67-75.
79. Kato S, Aoyama M, Kakita H, Hida H, Kato I, et al. (2011) Endogenous erythropoietin from astrocyte protects the oligodendrocyte precursor cell against hypoxic and reoxygenation injury. J Neurosci Res 89: 1566-1574.
80. Kigerl KA, Ankeny DP, Garg SK, Wei P, Guan Z, et al. (2012) System x(c)(-) regulates microglia and macrophage glutamate excitotoxicity in vivo. Exp Neurol 233: 333-341.
81. L'Episcopo F, Tirolo C, Testa N, Caniglia S, Morale MC, et al. (2012) Plasticity of Subventricular Zone Neuroprogenitors in MPTP (1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine) Mouse Model of Parkinson's Disease Involves Cross Talk between Inflammatory and Wnt/beta-Catenin Signaling Pathways: Functional Consequences for Neuroprotection and Repair. J Neurosci 32: 2062-2085.
82. Shang YC, Chong ZZ, Hou J, Maiese K, (2009) FoxO3a governs early microglial proliferation and employs mitochondrial depolarization with caspase 3, 8, and 9 cleavage during oxidant induced apoptosis. Curr Neurovasc Res 6: 223-238.
83. Shang YC, Chong ZZ, Hou J, Maiese K, (2010) Wnt1, FoxO3a, and NF-kappaB oversee microglial integrity and activation during oxidant stress. Cell Signal 22: 1317-1329.
84. Hong YK, Lee S, Park SH, Lee JH, Han SY, et al. (2012) Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer's disease model. Biochem Biophys Res Commun 419: 49-53.
85. Liu T, Jin H, Sun QR, Xu JH, Hu HT, (2010) The neuroprotective effects of tanshinone IIA on beta-amyloid-induced toxicity in rat cortical neurons. Neuropharmacology 59: 595-604.
86. Kollensperger M, Krismer F, Pallua A, Stefanova N, Poewe W, et al. (2011) Erythropoietin is neuroprotective in a transgenic mouse model of multiple system atrophy. Mov Disord 26: 507-515.
87. Kook YH, Ka M, Um M, (2011) Neuroprotective cytokines repress PUMA induction in the 1-methyl-4-phenylpyridinium (MPP(+)) model of Parkinson's disease. Biochem Biophys Res Commun 411: 370-374.
88. Ioka T, Tsuruoka S, Ito C, Iwaguro H, Asahara T, et al. (2009) Hypertension induced by erythropoietin has a correlation with truncated erythropoietin receptor mRNA in endothelial progenitor cells of hemodialysis patients. Clin Pharmacol Ther 86: 154-159.
89. Maiese K, Li F, Chong ZZ, (2005) New avenues of exploration for erythropoietin. Jama 293: 90-95.
90. Lanfranconi S, Locatelli F, Corti S, Candelise L, Comi GP, et al. (2011) Growth factors in ischemic stroke. J Cell Mol Med 15: 1645-1687.
91. Maiese K, Chong ZZ, Shang YC, (2008) Raves and risks for erythropoietin. Cytokine Growth Factor Rev 19: 145-155.
92. Mastromarino V, Volpe M, Musumeci MB, Autore C, Conti E, (2011) Erythropoietin and the heart: facts and perspectives. Clin Sci (Lond) 120: 51-63.
93. Hardee ME, Cao Y, Fu P, Jiang X, Zhao Y, et al. (2007) Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE 2: e549.
94. Hedley BD, Allan AL, Xenocostas A, (2011) The role of erythropoietin and erythropoiesis-stimulating agents in tumor progression. Clin Cancer Res 17: 6373-6380.
95. Lombardero M, Kovacs K, Scheithauer BW, (2011) Erythropoietin: a hormone with multiple functions. Pathobiology 78: 41-53.
96. Maiese K, Li F, Chong ZZ, (2005) Erythropoietin and cancer. JAMA 293: 1858-1859.
97. Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, et al. (2011) Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 121: 4477-4490.
98. Andreucci M, Fuiano G, Presta P, Lucisano G, Leone F, et al. (2009) Downregulation of cell survival signalling pathways and increased cell damage in hydrogen peroxide-treated human renal proximal tubular cells by alpha-erythropoietin. Cell Prolif 42: 554-561.
99. Di Nardo A, Kramvis I, Cho N, Sadowski A, Meikle L, et al. (2009) Tuberous sclerosis complex activity is required to control neuronal stress responses in an mTOR-dependent manner. J Neurosci 29: 5926-5937.
100. Jastrzebski K, Hannan KM, Tchoubrieva EB, Hannan RD, Pearson RB, (2007) Coordinate regulation of ribosome biogenesis and function by the ribosomal protein S6 kinase, a key mediator of mTOR function. Growth Factors 25: 209-226.
101. Hou G, Xue L, Lu Z, Fan T, Tian F, et al. (2007) An activated mTOR/p70S6K signaling pathway in esophageal squamous cell carcinoma cell lines and inhibition of the pathway by rapamycin and siRNA against mTOR. Cancer Lett 253: 236-248.
102. Pastor MD, Garcia-Yebenes I, Fradejas N, Perez-Ortiz JM, Mora-Lee S, et al. (2009) mTOR/S6 kinase pathway contributes to astrocyte survival during ischemia. J Biol Chem 284: 22067-22078.
103. Zhang D, Contu R, Latronico MV, Zhang J, Rizzi R, et al. (2010) MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 120: 2805-2816.
104. Chong ZZ, Maiese K, (2007) The Src homology 2 domain tyrosine phosphatases SHP-1 and SHP-2: diversified control of cell growth, inflammation, and injury. Histol Histopathol 22: 1251-1267.
105. Fokas E, Yoshimura M, Prevo R, Higgins G, Hackl W, et al. (2012) NVP-BEZ235 and NVP-BGT226, dual phosphatidylinositol 3-kinase/Mammalian target of rapamycin inhibitors, enhance tumor and endothelial cell radiosensitivity. Radiat Oncol 7: 48.
106. Hou J, Chong ZZ, Shang YC, Maiese K, (2010) Early apoptotic vascular signaling is determined by Sirt1 through nuclear shuttling, forkhead trafficking, bad, and mitochondrial caspase activation. Curr Neurovasc Res 7: 95-112.
107. Kang JQ, Chong ZZ, Maiese K, (2003) Critical role for Akt1 in the modulation of apoptotic phosphatidylserine exposure and microglial activation. Mol Pharmacol 64: 557-569.
108. Chen JX, Tuo Q, Liao DF, Zeng H, (2012) Inhibition of Protein Tyrosine Phosphatase Improves Angiogenesis via Enhancing Ang-1/Tie-2 Signaling in Diabetes. Exp Diabetes Res 2012: 836759.
109. Deblon N, Bourgoin L, Veyrat-Durebex C, Peyrou M, Vinciguerra M, et al. (2012) Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats. Br J Pharmacol 165: 2325-2340.
110. Hou J, Chong ZZ, Shang YC, Maiese K, (2010) FoxO3a governs early and late apoptotic endothelial programs during elevated glucose through mitochondrial and caspase signaling. Mol Cell Endocrinol 321: 194-206.
111. Maiese K, Chong ZZ, Hou J, Shang YC, (2009) The vitamin nicotinamide: translating nutrition into clinical care. Molecules 14: 3446-3485.
112. Chong ZZ, Li F, Maiese K, (2005) Activating Akt and the brain's resources to drive cellular survival and prevent inflammatory injury. Histol Histopathol 20: 299-315.
113. Chung CY, Park YL, Song YA, Myung E, Kim KY, et al. (2012) Knockdown of RON Inhibits AP-1 Activity and Induces Apoptosis and Cell Cycle Arrest Through the Modulation of Akt/FoxO Signaling in Human Colorectal Cancer Cells. Dig Dis Sci 57: 371-380.
114. Janku F, Wheler JJ, Westin SN, Moulder SL, Naing A, et al. (2012) PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J Clin Oncol 30: 777-782.
115. Eliopoulos N, Zhao J, Forner K, Birman E, Young YK, et al. (2011) Erythropoietin Gene-enhanced Marrow Mesenchymal Stromal Cells Decrease Cisplatin-induced Kidney Injury and Improve Survival of Allogeneic Mice. Mol Ther 19: 2072-2083.
116. Shen J, Wu Y, Xu JY, Zhang J, Sinclair SH, et al. (2010) ERK- and Akt-dependent neuroprotection by erythropoietin (EPO) against glyoxal-AGEs via modulation of Bcl-xL, Bax, and BAD. Invest Ophthalmol Vis Sci 51: 35-46.
117. Hernandez G, Lal H, Fidalgo M, Guerrero A, Zalvide J, et al. (2011) A novel cardioprotective p38-MAPK/mTOR pathway. Exp Cell Res 317: 2938-2949.
118. Magri L, Cambiaghi M, Cominelli M, Alfaro-Cervello C, Cursi M, et al. (2011) Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 9: 447-462.
119. Dormond O, Madsen JC, Briscoe DM, (2007) The effects of mTOR-Akt interactions on anti-apoptotic signaling in vascular endothelial cells. J Biol Chem 282: 23679-23686.
120. Maiese K, Chong ZZ, Shang YC, (2008) OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med 14: 219-227.
121. Thedieck K, Polak P, Kim ML, Molle KD, Cohen A, et al. (2007) PRAS40 and PRR5-like protein are new mTOR interactors that regulate apoptosis. PLoS One 2: e1217.
122. Maiese K, Chong ZZ, Hou J, Shang YC, (2010) Oxidative stress: Biomarkers and novel therapeutic pathways. Exp Gerontol 45: 217-234.
123. Sung JH, Kim MO, Koh PO, (2012) Nicotinamide Prevents the Down-Regulation of MEK/ERK/p90RSK Signaling Cascade in Brain Ischemic Injury. J Vet Med Sci 74: 35-41.
124. Troy CM, Akpan N, Jean YY, (2011) Regulation of caspases in the nervous system implications for functions in health and disease. Prog Mol Biol Transl Sci 99: 265-305.
125. Wang J, Sun P, Bao Y, Dou B, Song D, et al. (2012) Vitamin E renders protection to PC12 cells against oxidative damage and apoptosis induced by single-walled carbon nanotubes. Toxicol In Vitro 26: 32-41.
126. Dang J, Jia R, Tu Y, Xiao S, Ding G, (2010) Erythropoietin prevents reactive oxygen species generation and renal tubular cell apoptosis at high glucose level. Biomed Pharmacother 64: 681-685.
127. Wu Y, Shang Y, Sun S, Liang H, Liu R, (2007) Erythropoietin prevents PC12 cells from 1-methyl-4-phenylpyridinium ion-induced apoptosis via the Akt/GSK-3beta/caspase-3 mediated signaling pathway. Apoptosis 12: 1365-1375.