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系統識別號 U0026-1908201510592600
論文名稱(中文) 前胸腺素在多囊性腎病之病理生理角色
論文名稱(英文) The pathophysiological role of prothymosin α in polycystic kidney disease
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 103
學期 2
出版年 104
研究生(中文) 陳怡成
研究生(英文) Yi-Cheng Chen
學號 S58971081
學位類別 博士
語文別 英文
論文頁數 107頁
口試委員 指導教授-吳昭良
召集委員-賴明德
召集委員-林以行
召集委員-張文粲
口試委員-林清淵
口試委員-黃佩欣
中文關鍵字 前胸腺素 
英文關鍵字 prothymosin 
學科別分類
中文摘要 多囊性腎病是一個會在腎臟產生許多囊泡的遺傳缺失疾病。根據之前的報導,我們已經知道前胸腺素過量表現的基因轉殖小鼠會誘發多囊性腎病,然而前胸腺素在多囊腎病中過量表現之分子機轉仍然不清楚。在這裡,我們闡述了在多囊性腎病中,前胸腺素的上游及下游之分子機轉。我們發現了一個和發炎有關的TRAF6蛋白,其不管在小鼠的多囊腎動物模式或是臨床多囊腎病人中,均有較高的表現量。TRAF6蛋白可以催化前胸腺素的泛素化而導致其過量表現,另一方面,被誘導表現量升高的前胸腺素會造成廣泛的蛋白質乙醯化現象,伴隨之的STAT3蛋白易被乙醯化及高度活化。我們進一步使用兩個系統去證實在多囊腎病之囊泡形成過程中,我們的發現之重要性。第一:在細胞實驗中,給予TRAF6抑制劑可減少前胸腺素的表現;在動物實驗中,則可以有效的減緩多囊腎之囊泡生長。第二:我們利用體外的囊泡形成之分析實驗去證實,前胸腺素量表現所導致的囊泡形成是透過STAT3蛋白的活化。總結來說,多囊腎病的詳細病理基轉仍未被完全知曉,且目前並無有效的治療方法。本篇研究中,我們提出了TRAF6蛋白及前胸腺素在多囊腎病上的重要性,有助於更了解囊泡細胞的分子生理機轉,對於提供給多囊腎病的治療策略是重要的。
英文摘要 Polycystic kidney disease (PKD) is a genetic disorder characterized by the formation of multiple renal cysts. Previous research shows that the transgenic overexpression of prothymosin α (ProT) induces the development of PKD; however, the molecular mechanism underlying the overexpression of ProT in PKD remains unclear. Here, we elucidate the upstream and downstream molecular mechanism of ProT in PKD. We find an inflammation-associated molecule, TNF receptor-associated factor 6 (TRAF6), is increased in both the mouse PKD model and in the kidney of patient with PKD. TRAF6 is able to enhance the expression of ProT through catalyzing the ubiquitination of ProT, and, on the other hand, the up-regulated ProT induces a global protein acetylation, which is accompanied by the acetylation and hyper activation of STAT3. We further used two systems to determine the significance of our study in cyst formation in PKD. 1) Administration of TRAF6 inhibitor is able to reduce the expression of ProT in vitro and efficiently slows the growth of renal cyst in PKD. 2) We performed a cyst formation assay in vitro to demonstrate that overexpression of ProT induces cyst formation through the activation of STAT3. In summary, the detailed pathological mechanism of PKD is not fully understood, and there is not yet an effective therapeutic approach. In this study, we describe the significance of TRAF6 and ProT in PKD, thus helping to clarify the molecular mechanisms of cystic physiology, and this will knowledge will contribute to developing new therapeutic strategies for PKD.
論文目次 中文摘要 II
ABSTRACT III
誌謝 IV
CONTENTS V
INDEX OF FIGURES IX
ABBREVIATIONS XII
BACKGROUND 1
I. Prothymosin α (ProT) 1
I-1 Introduction 1
I-2 The biological roles of ProT 2
I-2.1 Immune modulation 2
I-2.2 Proliferation 3
I-2.3 Anti-apoptosis 4
I-2.4 Oxidative stress 5
I-2.5 Cancer biology 6
I-2.6 Gene regulation 7
I-3 ProT transgenic mice 9
II. Polycystic kidney disease (PKD) 10
II-1 Introduction 10
II-2 Cellular pathophysiology of PKD 11
II-2.1 Proliferation and apoptosis 12
II-2.2 Cell polarity 12
II-2.3 Ciliopathy 13
II-2.4 Interstitial fibrosis in PKD 14
II-3 Molecular basis of PKD. 15
II-3.1 cAMP 15
II-3.2 Proteolysis of polycystin-1 16
II-4 Therapeutic approach 17
RATIONALES AND SPECIFIC AIMS 19
MATERIALS AND METHODS 22
1. Plasmid manipulation 22
2. Cell culture 23
3. Plasmids 24
4. Mice and clinical samples 27
5. Genotyping for transgenic mice 27
6. Reporter assay 28
7. Viral vector usage, virus infection, stable cell line generation 29
8. Immunoblotting and Co-immunoprecipitation 30
9. Immunohistochemistry and immunofluorescence 31
10. RNA extraction and quantitative PCR 32
11. Tubulogenesis assay 33
12. Statistical analyses 33
RESULTS 34
1. Aberrant overexpression of ProT in PKD. 34
2. Inhibition of ProT is sufficient to attenuate cystogenesis in vitro. 35
3. Increased protein acetylation in PKD. 35
4. Acetylation of STAT3 in PKD. 37
5. ProT induces STAT3 activation. 39
6. STAT3 activation in Pkd1 defective cells. 40
7. Inhibition of STAT3 activation in ProT overexpressing MDCK cells reduces cyst formation. 41
8. Immunostaining for clinical samples 42
9. TRAF6 increases ProT expression 42
10. TRAF6 mediates ProT ubiquitination 43
11. Increased TRAF6 in PKD. 44
12. Therapeutic effects of TRAF6 inhibitor in mouse PKD. 45
DISCUSSION 47
CONCLUSION 55
REFERENCES 57
FIGURES AND LEGENDS 72

參考文獻 1. Haritos, AA, Tsolas, O, Horecker, BL: Distribution of prothymosin alpha in rat tissues. Proc Natl Acad Sci U S A, 81: 1391-1393, 1984.
2. Makarova, T, Grebenshikov, N, Egorov, C, Vartapetian, A, Bogdanov, A: Prothymosin alpha is an evolutionary conserved protein covalently linked to a small RNA. FEBS Lett, 257: 247-250, 1989.
3. Haritos, AA, Blacher, R, Stein, S, Caldarella, J, Horecker, BL: Primary structure of rat thymus prothymosin alpha. Proc Natl Acad Sci U S A, 82: 343-346, 1985.
4. Economou, M, Seferiadis, K, Frangou-Lazaridis, M, Horecker, BL, Tsolas, O: Isolation and partial characterization of prothymosin alpha from porcine tissues. FEBS Lett, 233: 342-346, 1988.
5. Baxevanis, CN, Frillingos, S, Seferiadis, K, Reclos, GJ, Arsenis, P, Katsiyiannis, A, Anastasopoulos, E, Tsolas, O, Papamichail, M: Enhancement of human T lymphocyte function by prothymosin alpha: increased production of interleukin-2 and expression of interleukin-2 receptors in normal human peripheral blood T lymphocytes. Immunopharmacol Immunotoxicol, 12: 595-617, 1990.
6. Baxevanis, CN, Thanos, D, Reclos, GJ, Anastasopoulos, E, Tsokos, GC, Papamatheakis, J, Papamichail, M: Prothymosin alpha enhances human and murine MHC class II surface antigen expression and messenger RNA accumulation. J Immunol, 148: 1979-1984, 1992.
7. Cordero, OJ, Sarandeses, CS, Lopez, JL, Nogueira, M: Prothymosin alpha enhances human natural killer cell cytotoxicity: role in mediating signals for NK activity. Lymphokine Cytokine Res, 11: 277-285, 1992.
8. Lopez-Rodriguez, JL, Cordero, OJ, Sarandeses, C, Vinuela, J, Nogueira, M: Interleukin-2 killer cells: in vitro evaluation of combination with prothymosin alpha. Lymphokine Cytokine Res, 13: 175-182, 1994.
9. Shiau, AL, Lin, PR, Chang, MY, Wu, CL: Retrovirus-mediated transfer of prothymosin gene inhibits tumor growth and prolongs survival in murine bladder cancer. Gene Ther, 8: 1609-1617, 2001.
10. Mosoian, A, Teixeira, A, Burns, CS, Sander, LE, Gusella, GL, He, C, Blander, JM, Klotman, P, Klotman, ME: Prothymosin-alpha inhibits HIV-1 via Toll-like receptor 4-mediated type I interferon induction. Proc Natl Acad Sci U S A, 107: 10178-10183, 2010.
11. Samara, P, Ioannou, K, Neagu, M, Arnogiannaki, N, Ardavanis, A, Voelter, W, Tsitsilonis, O: The C-terminal decapeptide of prothymosin alpha is responsible for its stimulatory effect on the functions of human neutrophils in vitro. Int Immunopharmacol, 15: 50-57, 2013.
12. Barcia, MG, Castro, JM, Jullien, CD, Freire, M: Prothymosin alpha is phosphorylated in proliferating stimulated cells. J Biol Chem, 268: 4704-4708, 1993.
13. Vareli, K, Tsolas, O, Frangou-Lazaridis, M: Regulation of prothymosin alpha during the cell cycle. Eur J Biochem, 238: 799-806, 1996.
14. Bustelo, XR, Otero, A, Gomez-Marquez, J, Freire, M: Expression of the rat prothymosin alpha gene during T-lymphocyte proliferation and liver regeneration. J Biol Chem, 266: 1443-1447, 1991.
15. Rodriguez, P, Vinuela, JE, Alvarez-Fernandez, L, Buceta, M, Vidal, A, Dominguez, F, Gomez-Marquez, J: Overexpression of prothymosin alpha accelerates proliferation and retards differentiation in HL-60 cells. Biochem J, 331 ( Pt 3): 753-761, 1998.
16. Rodriguez, P, Vinuela, JE, Alvarez-Fernandez, L, Gomez-Marquez, J: Prothymosin alpha antisense oligonucleotides induce apoptosis in HL-60 cells. Cell Death Differ, 6: 3-5, 1999.
17. Wu, CL, Shiau, AL, Lin, CS: Prothymosin alpha promotes cell proliferation in NIH3T3 cells. Life Sci, 61: 2091-2101, 1997.
18. Hengartner, MO: The biochemistry of apoptosis. Nature, 407: 770-776, 2000.
19. Jiang, X, Kim, HE, Shu, H, Zhao, Y, Zhang, H, Kofron, J, Donnelly, J, Burns, D, Ng, SC, Rosenberg, S, Wang, X: Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science, 299: 223-226, 2003.
20. Letsas, KP, Frangou-Lazaridis, M, Skyrlas, A, Tsatsoulis, A, Malamou-Mitsi, V: Transcription factor-mediated proliferation and apoptosis in benign and malignant thyroid lesions. Pathol Int, 55: 694-702, 2005.
21. Evstafieva, AG, Belov, GA, Kalkum, M, Chichkova, NV, Bogdanov, AA, Agol, VI, Vartapetian, AB: Prothymosin alpha fragmentation in apoptosis. FEBS Lett, 467: 150-154, 2000.
22. Evstafieva, AG, Belov, GA, Rubtsov, YP, Kalkum, M, Joseph, B, Chichkova, NV, Sukhacheva, EA, Bogdanov, AA, Pettersson, RF, Agol, VI, Vartapetian, AB: Apoptosis-related fragmentation, translocation, and properties of human prothymosin alpha. Exp Cell Res, 284: 211-223, 2003.
23. Markova, OV, Evstafieva, AG, Mansurova, SE, Moussine, SS, Palamarchuk, LA, Pereverzev, MO, Vartapetian, AB, Skulachev, VP: Cytochrome c is transformed from anti- to pro-oxidant when interacting with truncated oncoprotein prothymosin alpha. Biochim Biophys Acta, 1557: 109-117, 2003.
24. Pai, CW, Chen, YH: Transgenic expression of prothymosin alpha on zebrafish epidermal cells promotes proliferation and attenuates UVB-induced apoptosis. Transgenic Res, 19: 655-665, 2010.
25. Cannavo, A, Rengo, G, Liccardo, D, Pironti, G, Scimia, MC, Scudiero, L, De Lucia, C, Ferrone, M, Leosco, D, Zambrano, N, Koch, WJ, Trimarco, B, Esposito, G: Prothymosin alpha protects cardiomyocytes against ischemia-induced apoptosis via preservation of Akt activation. Apoptosis, 18: 1252-1261, 2013.
26. Lin, YT, Lu, HP, Chao, CC: Oncogenic c-Myc and prothymosin-alpha protect hepatocellular carcinoma cells against sorafenib-induced apoptosis. Biochem Pharmacol, 93: 110-124, 2015.
27. Dhakshinamoorthy, S, Long, DJ, 2nd, Jaiswal, AK: Antioxidant regulation of genes encoding enzymes that detoxify xenobiotics and carcinogens. Curr Top Cell Regul, 36: 201-216, 2000.
28. Kobayashi, M, Yamamoto, M: Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul, 46: 113-140, 2006.
29. Niture, SK, Jaiswal, AK: Prothymosin-alpha mediates nuclear import of the INrf2/Cul3 Rbx1 complex to degrade nuclear Nrf2. J Biol Chem, 284: 13856-13868, 2009.
30. Wu, CG, Habib, NA, Mitry, RR, Reitsma, PH, van Deventer, SJ, Chamuleau, RA: Overexpression of hepatic prothymosin alpha, a novel marker for human hepatocellular carcinoma. Br J Cancer, 76: 1199-1204, 1997.
31. Ioannou, K, Samara, P, Livaniou, E, Derhovanessian, E, Tsitsilonis, OE: Prothymosin alpha: a ubiquitous polypeptide with potential use in cancer diagnosis and therapy. Cancer Immunol Immunother, 61: 599-614, 2012.
32. Dominguez, F, Magdalena, C, Cancio, E, Roson, E, Paredes, J, Loidi, L, Zalvide, J, Fraga, M, Forteza, J, Regueiro, BJ, et al.: Tissue concentrations of prothymosin alpha: a novel proliferation index of primary breast cancer. Eur J Cancer, 29A: 893-897, 1993.
33. Magdalena, C, Dominguez, F, Loidi, L, Puente, JL: Tumour prothymosin alpha content, a potential prognostic marker for primary breast cancer. Br J Cancer, 82: 584-590, 2000.
34. Eilers, M, Schirm, S, Bishop, JM: The MYC protein activates transcription of the alpha-prothymosin gene. EMBO J, 10: 133-141, 1991.
35. Gaubatz, S, Meichle, A, Eilers, M: An E-box element localized in the first intron mediates regulation of the prothymosin alpha gene by c-myc. Mol Cell Biol, 14: 3853-3862, 1994.
36. Bianco, NR, Montano, MM: Regulation of prothymosin alpha by estrogen receptor alpha: molecular mechanisms and relevance in estrogen-mediated breast cell growth. Oncogene, 21: 5233-5244, 2002.
37. Martini, PG, Katzenellenbogen, BS: Regulation of prothymosin alpha gene expression by estrogen in estrogen receptor-containing breast cancer cells via upstream half-palindromic estrogen response element motifs. Endocrinology, 142: 3493-3501, 2001.
38. Martini, PG, Delage-Mourroux, R, Kraichely, DM, Katzenellenbogen, BS: Prothymosin alpha selectively enhances estrogen receptor transcriptional activity by interacting with a repressor of estrogen receptor activity. Mol Cell Biol, 20: 6224-6232, 2000.
39. Gomez-Marquez, J, Rodriguez, P: Prothymosin alpha is a chromatin-remodelling protein in mammalian cells. Biochem J, 333 ( Pt 1): 1-3, 1998.
40. Karetsou, Z, Sandaltzopoulos, R, Frangou-Lazaridis, M, Lai, CY, Tsolas, O, Becker, PB, Papamarcaki, T: Prothymosin alpha modulates the interaction of histone H1 with chromatin. Nucleic Acids Res, 26: 3111-3118, 1998.
41. Knight, JS, Lan, K, Subramanian, C, Robertson, ES: Epstein-Barr virus nuclear antigen 3C recruits histone deacetylase activity and associates with the corepressors mSin3A and NCoR in human B-cell lines. J Virol, 77: 4261-4272, 2003.
42. Subramanian, C, Hasan, S, Rowe, M, Hottiger, M, Orre, R, Robertson, ES: Epstein-Barr virus nuclear antigen 3C and prothymosin alpha interact with the p300 transcriptional coactivator at the CH1 and CH3/HAT domains and cooperate in regulation of transcription and histone acetylation. J Virol, 76: 4699-4708, 2002.
43. Subramanian, C, Knight, JS, Robertson, ES: The Epstein Barr nuclear antigen EBNA3C regulates transcription, cell transformation and cell migration. Front Biosci, 7: d704-716, 2002.
44. Kobayashi, T, Wang, T, Maezawa, M, Kobayashi, M, Ohnishi, S, Hatanaka, K, Hige, S, Shimizu, Y, Kato, M, Asaka, M, Tanaka, J, Imamura, M, Hasegawa, K, Tanaka, Y, Brachmann, RK: Overexpression of the oncoprotein prothymosin alpha triggers a p53 response that involves p53 acetylation. Cancer Res, 66: 3137-3144, 2006.
45. Su, BH, Tseng, YL, Shieh, GS, Chen, YC, Shiang, YC, Wu, P, Li, KJ, Yen, TH, Shiau, AL, Wu, CL: Prothymosin alpha overexpression contributes to the development of pulmonary emphysema. Nat Commun, 4: 1906, 2013.
46. Li, KJ, Shiau, AL, Chiou, YY, Yo, YT, Wu, CL: Transgenic overexpression of prothymosin alpha induces development of polycystic kidney disease. Kidney Int, 67: 1710-1722, 2005.
47. Riella, C, Czarnecki, PG, Steinman, TI: Therapeutic advances in the treatment of polycystic kidney disease. Nephron Clin Pract, 128: 297-302, 2014.
48. Wilson, PD: Polycystic kidney disease. N Engl J Med, 350: 151-164, 2004.
49. Harris, PC, Bae, KT, Rossetti, S, Torres, VE, Grantham, JJ, Chapman, AB, Guay-Woodford, LM, King, BF, Wetzel, LH, Baumgarten, DA, Kenney, PJ, Consugar, M, Klahr, S, Bennett, WM, Meyers, CM, Zhang, QJ, Thompson, PA, Zhu, F, Miller, JP: Cyst number but not the rate of cystic growth is associated with the mutated gene in autosomal dominant polycystic kidney disease. J Am Soc Nephrol, 17: 3013-3019, 2006.
50. Hanaoka, K, Qian, F, Boletta, A, Bhunia, AK, Piontek, K, Tsiokas, L, Sukhatme, VP, Guggino, WB, Germino, GG: Co-assembly of polycystin-1 and -2 produces unique cation-permeable currents. Nature, 408: 990-994, 2000.
51. Casuscelli, J, Schmidt, S, DeGray, B, Petri, ET, Celic, A, Folta-Stogniew, E, Ehrlich, BE, Boggon, TJ: Analysis of the cytoplasmic interaction between polycystin-1 and polycystin-2. Am J Physiol Renal Physiol, 297: F1310-1315, 2009.
52. Koulen, P, Cai, Y, Geng, L, Maeda, Y, Nishimura, S, Witzgall, R, Ehrlich, BE, Somlo, S: Polycystin-2 is an intracellular calcium release channel. Nat Cell Biol, 4: 191-197, 2002.
53. Woo, D: Apoptosis and loss of renal tissue in polycystic kidney diseases. N Engl J Med, 333: 18-25, 1995.
54. Veis, DJ, Sorenson, CM, Shutter, JR, Korsmeyer, SJ: Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell, 75: 229-240, 1993.
55. Du, J, Wilson, PD: Abnormal polarization of EGF receptors and autocrine stimulation of cyst epithelial growth in human ADPKD. Am J Physiol, 269: C487-495, 1995.
56. Wilson, PD, Devuyst, O, Li, X, Gatti, L, Falkenstein, D, Robinson, S, Fambrough, D, Burrow, CR: Apical plasma membrane mispolarization of NaK-ATPase in polycystic kidney disease epithelia is associated with aberrant expression of the beta2 isoform. Am J Pathol, 156: 253-268, 2000.
57. Badano, JL, Mitsuma, N, Beales, PL, Katsanis, N: The ciliopathies: an emerging class of human genetic disorders. Annu Rev Genomics Hum Genet, 7: 125-148, 2006.
58. Abdul-Majeed, S, Nauli, SM: Polycystic diseases in visceral organs. Obstet Gynecol Int, 2011: 609370, 2011.
59. Chapman, AB, Stepniakowski, K, Rahbari-Oskoui, F: Hypertension in autosomal dominant polycystic kidney disease. Adv Chronic Kidney Dis, 17: 153-163, 2010.
60. Barr, MM, Sternberg, PW: A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature, 401: 386-389, 1999.
61. Nauli, SM, Rossetti, S, Kolb, RJ, Alenghat, FJ, Consugar, MB, Harris, PC, Ingber, DE, Loghman-Adham, M, Zhou, J: Loss of polycystin-1 in human cyst-lining epithelia leads to ciliary dysfunction. J Am Soc Nephrol, 17: 1015-1025, 2006.
62. Nauli, SM, Alenghat, FJ, Luo, Y, Williams, E, Vassilev, P, Li, X, Elia, AE, Lu, W, Brown, EM, Quinn, SJ, Ingber, DE, Zhou, J: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet, 33: 129-137, 2003.
63. AbouAlaiwi, WA, Takahashi, M, Mell, BR, Jones, TJ, Ratnam, S, Kolb, RJ, Nauli, SM: Ciliary polycystin-2 is a mechanosensitive calcium channel involved in nitric oxide signaling cascades. Circ Res, 104: 860-869, 2009.
64. Hassane, S, Leonhard, WN, van der Wal, A, Hawinkels, LJ, Lantinga-van Leeuwen, IS, ten Dijke, P, Breuning, MH, de Heer, E, Peters, DJ: Elevated TGFbeta-Smad signalling in experimental Pkd1 models and human patients with polycystic kidney disease. J Pathol, 222: 21-31, 2010.
65. Nakamura, T, Ushiyama, C, Suzuki, S, Ebihara, I, Shimada, N, Koide, H: Elevation of serum levels of metalloproteinase-1, tissue inhibitor of metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase-9 in polycystic kidney disease. Am J Nephrol, 20: 32-36, 2000.
66. Qi, W, Chen, X, Poronnik, P, Pollock, CA: The renal cortical fibroblast in renal tubulointerstitial fibrosis. Int J Biochem Cell Biol, 38: 1-5, 2006.
67. Rees, S, Kittikulsuth, W, Roos, K, Strait, KA, Van Hoek, A, Kohan, DE: Adenylyl cyclase 6 deficiency ameliorates polycystic kidney disease. J Am Soc Nephrol, 25: 232-237, 2014.
68. Wuebken, A, Schmidt-Ott, KM: WNT/beta-catenin signaling in polycystic kidney disease. Kidney Int, 80: 135-138, 2011.
69. Taurin, S, Sandbo, N, Qin, Y, Browning, D, Dulin, NO: Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase. J Biol Chem, 281: 9971-9976, 2006.
70. Lancaster, MA, Gleeson, JG: Cystic kidney disease: the role of Wnt signaling. Trends Mol Med, 16: 349-360, 2010.
71. Ye, M, Grantham, JJ: The secretion of fluid by renal cysts from patients with autosomal dominant polycystic kidney disease. N Engl J Med, 329: 310-313, 1993.
72. Hanaoka, K, Guggino, WB: cAMP regulates cell proliferation and cyst formation in autosomal polycystic kidney disease cells. J Am Soc Nephrol, 11: 1179-1187, 2000.
73. Yamaguchi, T, Pelling, JC, Ramaswamy, NT, Eppler, JW, Wallace, DP, Nagao, S, Rome, LA, Sullivan, LP, Grantham, JJ: cAMP stimulates the in vitro proliferation of renal cyst epithelial cells by activating the extracellular signal-regulated kinase pathway. Kidney Int, 57: 1460-1471, 2000.
74. Distefano, G, Boca, M, Rowe, I, Wodarczyk, C, Ma, L, Piontek, KB, Germino, GG, Pandolfi, PP, Boletta, A: Polycystin-1 regulates extracellular signal-regulated kinase-dependent phosphorylation of tuberin to control cell size through mTOR and its downstream effectors S6K and 4EBP1. Mol Cell Biol, 29: 2359-2371, 2009.
75. Spirli, C, Okolicsanyi, S, Fiorotto, R, Fabris, L, Cadamuro, M, Lecchi, S, Tian, X, Somlo, S, Strazzabosco, M: ERK1/2-dependent vascular endothelial growth factor signaling sustains cyst growth in polycystin-2 defective mice. Gastroenterology, 138: 360-371 e367, 2010.
76. Chauvet, V, Tian, X, Husson, H, Grimm, DH, Wang, T, Hiesberger, T, Igarashi, P, Bennett, AM, Ibraghimov-Beskrovnaya, O, Somlo, S, Caplan, MJ: Mechanical stimuli induce cleavage and nuclear translocation of the polycystin-1 C terminus. J Clin Invest, 114: 1433-1443, 2004.
77. Talbot, JJ, Shillingford, JM, Vasanth, S, Doerr, N, Mukherjee, S, Kinter, MT, Watnick, T, Weimbs, T: Polycystin-1 regulates STAT activity by a dual mechanism. Proc Natl Acad Sci U S A, 108: 7985-7990, 2011.
78. Merrick, D, Chapin, H, Baggs, JE, Yu, Z, Somlo, S, Sun, Z, Hogenesch, JB, Caplan, MJ: The gamma-secretase cleavage product of polycystin-1 regulates TCF and CHOP-mediated transcriptional activation through a p300-dependent mechanism. Dev Cell, 22: 197-210, 2012.
79. Kim, H, Jeong, W, Ahn, K, Ahn, C, Kang, S: Siah-1 interacts with the intracellular region of polycystin-1 and affects its stability via the ubiquitin-proteasome pathway. J Am Soc Nephrol, 15: 2042-2049, 2004.
80. Kim, H, Kang, AY, Ko, AR, Park, HC, So, I, Park, JH, Cheong, HI, Hwang, YH, Ahn, C: Calpain-mediated Proteolysis of Polycystin-1 C-terminus Induces JAK2 and ERK signal Alterations. Exp Cell Res, 2013.
81. Dere, R, Wilson, PD, Sandford, RN, Walker, CL: Carboxy terminal tail of polycystin-1 regulates localization of TSC2 to repress mTOR. PLoS One, 5: e9239, 2010.
82. Lal, M, Song, X, Pluznick, JL, Di Giovanni, V, Merrick, DM, Rosenblum, ND, Chauvet, V, Gottardi, CJ, Pei, Y, Caplan, MJ: Polycystin-1 C-terminal tail associates with beta-catenin and inhibits canonical Wnt signaling. Hum Mol Genet, 17: 3105-3117, 2008.
83. Torres, VE, Wang, X, Qian, Q, Somlo, S, Harris, PC, Gattone, VH, 2nd: Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med, 10: 363-364, 2004.
84. Gattone, VH, 2nd, Wang, X, Harris, PC, Torres, VE: Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med, 9: 1323-1326, 2003.
85. Qian, Q, Du, H, King, BF, Kumar, S, Dean, PG, Cosio, FG, Torres, VE: Sirolimus reduces polycystic liver volume in ADPKD patients. J Am Soc Nephrol, 19: 631-638, 2008.
86. Wahl, PR, Serra, AL, Le Hir, M, Molle, KD, Hall, MN, Wuthrich, RP: Inhibition of mTOR with sirolimus slows disease progression in Han:SPRD rats with autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant, 21: 598-604, 2006.
87. Belibi, FA, Edelstein, CL: Novel targets for the treatment of autosomal dominant polycystic kidney disease. Expert Opin Investig Drugs, 19: 315-328, 2010.
88. Sweeney, WE, Jr., von Vigier, RO, Frost, P, Avner, ED: Src inhibition ameliorates polycystic kidney disease. J Am Soc Nephrol, 19: 1331-1341, 2008.
89. Trudel, M, D'Agati, V, Costantini, F: C-myc as an inducer of polycystic kidney disease in transgenic mice. Kidney Int, 39: 665-671, 1991.
90. Takakura, A, Nelson, EA, Haque, N, Humphreys, BD, Zandi-Nejad, K, Frank, DA, Zhou, J: Pyrimethamine inhibits adult polycystic kidney disease by modulating STAT signaling pathways. Hum Mol Genet, 20: 4143-4154, 2011.
91. Leonhard, WN, van der Wal, A, Novalic, Z, Kunnen, SJ, Gansevoort, RT, Breuning, MH, de Heer, E, Peters, DJ: Curcumin inhibits cystogenesis by simultaneous interference of multiple signaling pathways: in vivo evidence from a Pkd1-deletion model. Am J Physiol Renal Physiol, 300: F1193-1202, 2011.
92. de Heer, E, Peters, DJ: Innate immunity as a driving force in renal disease. Kidney Int, 73: 7-8, 2008.
93. Battini, L, Fedorova, E, Macip, S, Li, X, Wilson, PD, Gusella, GL: Stable knockdown of polycystin-1 confers integrin-alpha2beta1-mediated anoikis resistance. J Am Soc Nephrol, 17: 3049-3058, 2006.
94. Salmon, P, Trono, D: Production and titration of lentiviral vectors. Curr Protoc Hum Genet, Chapter 12: Unit 12 10, 2007.
95. Naviaux, RK, Costanzi, E, Haas, M, Verma, IM: The pCL vector system: rapid production of helper-free, high-titer, recombinant retroviruses. J Virol, 70: 5701-5705, 1996.
96. Sukhacheva, EA, Evstafieva, AG, Fateeva, TV, Shakulov, VR, Efimova, NA, Karapetian, RN, Rubtsov, YP, Vartapetian, AB: Sensing prothymosin alpha origin, mutations and conformation with monoclonal antibodies. J Immunol Methods, 266: 185-196, 2002.
97. Cotter, MA, 2nd, Robertson, ES: Modulation of histone acetyltransferase activity through interaction of epstein-barr nuclear antigen 3C with prothymosin alpha. Mol Cell Biol, 20: 5722-5735, 2000.
98. Balasubramanyam, K, Varier, RA, Altaf, M, Swaminathan, V, Siddappa, NB, Ranga, U, Kundu, TK: Curcumin, a novel p300/CREB-binding protein-specific inhibitor of acetyltransferase, represses the acetylation of histone/nonhistone proteins and histone acetyltransferase-dependent chromatin transcription. J Biol Chem, 279: 51163-51171, 2004.
99. Yuan, ZL, Guan, YJ, Chatterjee, D, Chin, YE: Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science, 307: 269-273, 2005.
100. Yang, CH, Murti, A, Baker, SJ, Frangou-Lazaridis, M, Vartapetian, AB, Murti, KG, Pfeffer, LM: Interferon induces the interaction of prothymosin-alpha with STAT3 and results in the nuclear translocation of the complex. Exp Cell Res, 298: 197-206, 2004.
101. Gattone, VH, 2nd: Prothymosin alpha as a cystogen. Kidney Int, 67: 2063-2064, 2005.
102. Yoo, CB, Jones, PA: Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov, 5: 37-50, 2006.
103. Van Bodegom, D, Saifudeen, Z, Dipp, S, Puri, S, Magenheimer, BS, Calvet, JP, El-Dahr, SS: The polycystic kidney disease-1 gene is a target for p53-mediated transcriptional repression. J Biol Chem, 281: 31234-31244, 2006.
104. Cao, Y, Semanchik, N, Lee, SH, Somlo, S, Barbano, PE, Coifman, R, Sun, Z: Chemical modifier screen identifies HDAC inhibitors as suppressors of PKD models. Proc Natl Acad Sci U S A, 106: 21819-21824, 2009.
105. Pugacheva, EN, Jablonski, SA, Hartman, TR, Henske, EP, Golemis, EA: HEF1-dependent Aurora A activation induces disassembly of the primary cilium. Cell, 129: 1351-1363, 2007.
106. Liu, W, Fan, LX, Zhou, X, Sweeney, WE, Jr., Avner, ED, Li, X: HDAC6 regulates epidermal growth factor receptor (EGFR) endocytic trafficking and degradation in renal epithelial cells. PLoS One, 7: e49418, 2012.
107. Zhou, X, Fan, LX, Sweeney, WE, Jr., Denu, JM, Avner, ED, Li, X: Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease. J Clin Invest, 123: 3084-3098, 2013.
108. Qin, S, Taglienti, M, Cai, L, Zhou, J, Kreidberg, JA: c-Met and NF-kappaB-dependent overexpression of Wnt7a and -7b and Pax2 promotes cystogenesis in polycystic kidney disease. J Am Soc Nephrol, 23: 1309-1318, 2012.
109. Kwon, SH, Nedvetsky, PI, Mostov, KE: Transcriptional profiling identifies TNS4 function in epithelial tubulogenesis. Curr Biol, 21: 161-166, 2011.
110. Takayama, H, LaRochelle, WJ, Sabnis, SG, Otsuka, T, Merlino, G: Renal tubular hyperplasia, polycystic disease, and glomerulosclerosis in transgenic mice overexpressing hepatocyte growth factor/scatter factor. Lab Invest, 77: 131-138, 1997.
111. Fattori, E, Della Rocca, C, Costa, P, Giorgio, M, Dente, B, Pozzi, L, Ciliberto, G: Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood, 83: 2570-2579, 1994.
112. Qin, S, Taglienti, M, Nauli, SM, Contrino, L, Takakura, A, Zhou, J, Kreidberg, JA: Failure to ubiquitinate c-Met leads to hyperactivation of mTOR signaling in a mouse model of autosomal dominant polycystic kidney disease. J Clin Invest, 120: 3617-3628, 2010.
113. Cowley, BD, Jr., Ricardo, SD, Nagao, S, Diamond, JR: Increased renal expression of monocyte chemoattractant protein-1 and osteopontin in ADPKD in rats. Kidney Int, 60: 2087-2096, 2001.
114. Ta, MH, Harris, DC, Rangan, GK: Role of interstitial inflammation in the pathogenesis of polycystic kidney disease. Nephrology (Carlton), 18: 317-330, 2013.
115. Lamothe, B, Besse, A, Campos, AD, Webster, WK, Wu, H, Darnay, BG: Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation. J Biol Chem, 282: 4102-4112, 2007.
116. Heyninck, K, Beyaert, R: The cytokine-inducible zinc finger protein A20 inhibits IL-1-induced NF-kappaB activation at the level of TRAF6. FEBS Lett, 442: 147-150, 1999.
117. Wertz, IE, O'Rourke, KM, Zhou, H, Eby, M, Aravind, L, Seshagiri, S, Wu, P, Wiesmann, C, Baker, R, Boone, DL, Ma, A, Koonin, EV, Dixit, VM: De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling. Nature, 430: 694-699, 2004.
118. Ibraghimov-Beskrovnaya, O, Natoli, TA: mTOR signaling in polycystic kidney disease. Trends Mol Med, 17: 625-633, 2011.
119. Shrikhande, GV, Scali, ST, da Silva, CG, Damrauer, SM, Csizmadia, E, Putheti, P, Matthey, M, Arjoon, R, Patel, R, Siracuse, JJ, Maccariello, ER, Andersen, ND, Monahan, T, Peterson, C, Essayagh, S, Studer, P, Guedes, RP, Kocher, O, Usheva, A, Veves, A, Kaczmarek, E, Ferran, C: O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null mice. PLoS One, 5: e14240, 2010.
120. Thivierge, C, Kurbegovic, A, Couillard, M, Guillaume, R, Cote, O, Trudel, M: Overexpression of PKD1 causes polycystic kidney disease. Mol Cell Biol, 26: 1538-1548, 2006.
121. Park, S, Pak, J, Jang, I, Cho, JW: Inhibition of mTOR affects protein stability of OGT. Biochem Biophys Res Commun, 453: 208-212, 2014.
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