Clinical and molecular insights into tuberous sclerosis complex renal disease

Pediatric Nephrology

Volumn 26, Issue 6, 2011, Pages 839-852

  Siroky, Brian J ^a   Yin, Hong ^a   Bissler, John J ^a  

^a CINCINNATI CHILDREN'S HOSPITAL MEDICAL CENTER   (United States)

Author keywords

Angiomyolipoma; Autophagy; Endoplasmic reticulum stress; mTORC1; Oncocytoma; Rapamycin; Renal cyst; Tuberous sclerosis complex

Indexed keywords

GROWTH FACTOR;

ANGIOMYOLIPOMA; AUTOPHAGY; CYTOLOGY; ENDOPLASMIC RETICULUM STRESS; EUKARYOTIC FLAGELLUM; HUMAN; KIDNEY DISEASE; KIDNEY POLYCYSTIC DISEASE; NEPHRECTOMY; PATHOLOGY; PATIENT CARE; PRIORITY JOURNAL; PROTEIN UNFOLDING; REVIEW; TUBEROUS SCLEROSIS;

ANGIOMYOLIPOMA; ANTIBIOTICS, ANTINEOPLASTIC; CHILD; HUMANS; KIDNEY DISEASES, CYSTIC; KIDNEY NEOPLASMS; PROTEINS; SIROLIMUS; TUBEROUS SCLEROSIS;

EID: 79959994425     PISSN: 0931041X     EISSN: 1432198X     Source Type: Journal    
DOI: 10.1007/s00467-010-1689-5     Document Type: Review

References (123)

1. Gomez M, Sampson J, Whittemore V (1999) Tuberous sclerosis. OxfordUniversity Press, New York
2. Shepherd CW, Gomez MR, Lie JT, Crowson CS (1991) Causes of death inpatients with tuberous sclerosis. Mayo Clin Proc 66:792-796
3. Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS,Reeve MP, Thiele E, Egelhoff JC, Kasprzyk-Obara J, Domanska-Pakiela D,Kwiatkowski DJ (2001) Mutational analysis in a cohort of 224 tuberoussclerosis patients indicates increased severity of TSC2, compared withTSC1, disease in multiple organs. Am J Hum Genet 68:64-80 (Pubitemid 32048362)
4. Ewalt DH, Sheffield E, Sparagana SP, Delgado MR, Roach ES (1998) Renallesion growth in children with tuberous sclerosis complex. J Urol160:141-145 (Pubitemid 29479447)
5. Rakowski SK, Winterkorn EB, Paul E, Steele DJ, Halpern EF, Thiele EA(2006) Renal manifestations of tuberous sclerosis complex: incidence,prognosis, and predictive factors. Kidney Int 70:1777-1782 (Pubitemid 44684809)
6. Patel V, Li L, Cobo-Stark P, Shao X, Somlo S, Lin F, Igarashi P (2008)Acute kidney injury and aberrant planar cell polarity induce cystformation in mice lacking renal cilia. Hum Mol Genet 17:1578-1590 (Pubitemid 351737162)
7. de Chadarevian JP, Legido A, Miles DK, Katsetos CD (2003) Epilepsy,atherosclerosis, myocardial infarction, and carbamazepine. J Child Neurol18:150-151 (Pubitemid 36432349)
8. Brook-Carter PT, Peral B, Ward CJ, Thompson P, Hughes J, Maheshwar MM,Nellist M, Gamble V, Harris PC, Sampson JR (1994) Deletion of the TSC2 andPKD1 genes associated with severe infantile polycystic kidney disease-acontiguous gene syndrome. Nat Genet 8:328-332 (Pubitemid 24375596)
9. Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J, Northrup H, Au KS, Lazarus R, Domanska-Pakiela D, Kotulska K, Jozwiak S, Kwiatkowski DJ(2007) Identification of 54 large deletions/duplications in TSC1 and TSC2using MLPA, and genotype-phenotype correlations. Hum Genet 121:389-400 (Pubitemid 46554675)
10. Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP, RavineD, Roy S, Haan E, Berstein J, Harris PC (1997) Renal cystic disease intuberous sclerosis: role of the polycystic kidney disease 1 gene. Am J HumGenet 61:843-851 (Pubitemid 27418458)
11. Valero Puerta JA, Medina Perez M, Valpuesta Fernandez I, SanchezGonzalez M (1999) A simple renal cyst, the origin of Wunderlich'ssyndrome. Arch Esp Urol 52:794-797
12. Bernstein J, Meyer R (1967) Parenchymal maldevelopment of the kidney.In: Kelley V (ed) Brennemann-Kelley practice of pediatrics. Harper, New York, pp 1-30
13. Potter E (1952) Pathology of the fetus and the newborn. Year BookMedical Publishers, Chicago
14. Ferrus A, Garcia-Bellido A (1976) Morphogenetic mutants detected inmitotic recombination clones. Nature 260:425-426
15. Siroky BJ, Czyzyk-Krzeska MF, Bissler JJ (2009) Renal involvement intuberous sclerosis complex and von Hippel-Lindau disease: shared diseasemechanisms? Nat Clin Pract Nephrol 5:143-156
16. Orskov B, Romming Sorensen V, Feldt-Rasmussen B, Strandgaard S (2010)Improved prognosis in patients with autosomal dominant polycystic kidneydisease in Denmark. Clin J Am Soc Nephrol. doi:10.2215/CJN.01460210
17. Masoumi A, Reed-Gitomer B, Kelleher C, Bekheirnia MR, Schrier RW(2008) Developments in the management of autosomal dominant polycystickidney disease. Ther Clin Risk Manag 4:393-407 (Pubitemid 351711998)
18. Jones AC, Daniells CE, Snell RG, Tachataki M, Idziaszczyk SA,Krawczak M, Sampson JR, Cheadle JP (1997) Molecular genetic and phenotypicanalysis reveals differences between TSC1 and TSC2 associated familial andsporadic tuberous sclerosis. Hum Mol Genet 6:2155-2216
19. Bernstein J (1993) Renal cystic disease in the tuberous sclerosis complex. Pediatr Nephrol 7:490-495 (Pubitemid 23258886)
20. Bissler JJ, Siroky BJ, Yin H (2010) Glomerulocystic kidney disease.Pediatr Nephrol 25:2049-2059
21. Sarnat HB, Flores-Sarnat L (2005) Embryology of the neural crest: itsinductive role in the neurocutaneous syndromes. J Child Neurol 20:637-643 (Pubitemid 43115359)
22. Hao Z, Guo C, Jiang X, Krueger S, Pietri T, Dufour S, Cone RE,O'Rourke J (2006) New transgenic evidence for a system of sympatheticaxons able to express tissue plasminogen activator (t-PA) withinarterial/arteriolar walls. Blood 108:200-202 (Pubitemid 43990629)
23. Henske EP (2005) Tuberous sclerosis and the kidney: from mesenchymeto epithelium, and beyond. Pediatr Nephrol 20:854-857 (Pubitemid 40909251)
24. Lin F, Yang W, Betten M, The BT, Yang XJ, French Kidney Cancer Study Group (2006) Expression of S-100 protein in renal cell neoplasms. HumPathol 37:462-470
25. Martignoni G, Pea M, Cossu Rocca P, Bonetti F (2003) Renal pathologyin the tuberous sclerosis complex. Pathology 35:505-512 (Pubitemid 38041286)
26. Bonetti F, PeaM, Martignoni G, Doglioni C, Zamboni G, Capelli P,Rimondi P, Andrion A (1994) Clear cell ("sugar") tumor of the lung is alesion strictly related toangiomyolipoma-the concept of a family oflesions characterized by the presence of the perivascular epithelioidcells (PEC). Pathology 26:230-236
27. El-Hashemite N, Walker V, Zhang H, Kwiatkowski DJ (2003) Loss of Tsc1or Tsc2 induces vascular endothelial growth factor production throughmammalian target of rapamycin. Cancer Res 63:5173-5177 (Pubitemid 37139823)
28. Karbowniczek M, Yu J, Henske EP (2003) Renal angiomyolipomas frompatients with sporadic lymphangiomyomatosis contain both neoplastic andnon-neoplastic vascular structures. Am J Pathol 162:491-500 (Pubitemid 36267856)
29. O'Callaghan FJ, Harris T, Joinson C, Bolton P, Noakes M, Presdee D,Renowden S, Shiell A, Martyn CN, Osborne JP (2004) The relation ofinfantile spasms, tubers, and intelligence in tuberous sclerosis complex.Arch Dis Child 89:530-533
30. McCullough DL, Scott R Jr, Seybold HM (1971) Renal angiomyolipoma(hamartoma): review of the literature and report of 7 cases. J Urol105:32-44
31. Stillwell TJ, Gomez MR, Kelalis PP (1987) Renal lesions in tuberoussclerosis. J Urol 138:477-481
32. Bernstein J, Robbins TO (1991) Renal involvement in tuberoussclerosis. Ann NY Acad Sci 615:36-49
33. Kennelly MJ, Grossman HB, Cho KJ (1994) Outcome analysis of 42 casesof renal angiomyolipoma [see comments]. J Urol 152:1988-1991 (Pubitemid 24354708)
34. Lemaitre L, Robert Y, Dubrulle F, Claudon M, Duhamel A, Danjou P, Mazeman E (1995) Renal angiomyolipoma: growth followed up with CT and/or US [see comments]. Radiology 197:598-602
35. Steiner MS, Goldman SM, Fishman EK, Marshall FF (1993) The natural history of renal angiomyolipoma. J Urol 150:1782-1786 (Pubitemid 24350798)
36. Pacheco-Rodriguez G, Moss J (2010) The role of chemokines in migration of metastatic-like lymphangioleiomyomatosis cells. Crit Rev Immunol 30:387-394
37. Ou YC, Wu HC, Yang CR, Chang CL, Hwang TI, Chang CH (1991) Renal angiomyolipoma: experience of 23 patients. Chung Hua I Hsueh Tsa Chih Taipei 48:217-223
38. Bissler JJ, Racadio J, Donnelly LF, Johnson MD (2002) Reduction of postembolization syndrome after ablation of renal angiomyolipoma. Am J Kidney Dis 39:966-971 (Pubitemid 34454215)
39. Casper KA, Donnelly LF, Chen B, Bissler JJ (2002) Tuberous sclerosis complex: renal imaging findings. Radiology 225:451-456 (Pubitemid 35239246)
40. Adler J, Greweldinger J, Litzky G (1984) "Macro" aneurysm in renal angiomyolipoma: two cases, with therapeutic embolization in one patient. Urol Radiol 6:201-203 (Pubitemid 15176575)
41. Kessler OJ, Gillon G, Neuman M, Engelstein D, Winkler H, Baniel J (1998) Management of renal angiomyolipoma: analysis of 15 cases. Eur Urol 33:572-575 (Pubitemid 28284802)
42. Mouded IM, Tolia BM, Bernie JE, Newman HR (1978) Symptomatic renal angiomyolipoma: report of 8 cases, 2 with spontaneous rupture. J Urol 119:684-688 (Pubitemid 8349490)
43. Pode D, Meretik S, Shapiro A, Caine M (1985) Diagnosis and management of renal angiomyolipoma. Urology 25:461-467 (Pubitemid 16073510)
44. Yamakado K, Tanaka N, Nakagawa T, Kobayashi S, Yanagawa M, Takeda K (2002) Renal angiomyolipoma: relationships between tumor size, aneurysm formation, and rupture. Radiology 225:78-82
45. Clarke A, Hancock E, Kingswood C, Osborne JP (1999) Endstage renal failure in adults with the tuberous sclerosis complex. Nephrol Dial Transplant 14:988-991 (Pubitemid 29155165)
46. Schillinger F, Montagnac R (1996) Chronic renal failure and its treatment in tuberous sclerosis. Nephrol Dial Transplant 11:481-485 (Pubitemid 26092787)
47. Fox CH, Voleti V, Khan LS, Murray B, Vassalotti J (2008) A quick guide to evidence-based chronic kidney disease care for the primary care physician. Postgrad Med 120:E01-E06
48. Patel U, Simpson E, Kingswood JC, Saggar-Malik AK (2005) Tuberose sclerosis complex: analysis of growth rates aids differentiation of renal cell carcinoma from atypical or minimal-fat-containing angiomyolipoma. Clin Radiol 60:665-673, discussion 663-664 (Pubitemid 40984061)
49. Eble JN, Amin MB, Young RH (1997) Epithelioid angiomyolipoma of the kidney: a report of five cases with a prominent and diagnostically confusing epithelioid smooth muscle component. Am J Surg Pathol 21:1123-1130
50. Mai KT, Perkins DG, Collins JP (1996) Epithelioid cell variant of renal angiomyolipoma [see comments]. Histopathology 28:277-280 (Pubitemid 26088738)
51. Lin CN, Chiang HS, Hsu SI, Huang AH, Chuang SS (1994) Renal angiomyolipoma with a prominent angiomatous component and extramedullary hematopoiesis: a case report. Chung Hua I Hsueh Tsa Chih Taipei 53:185-187
52. Tweeddale DN, Dawe CJ, McDonald JR (1955) Angiolipoleiomyoma of the kidney: report of a case with observations on histogenesis. Cancer 8:764-770
53. Obuz F, Karabay N, Secil M, Igci E, Kovanlikaya A, Yorukoglu K (2000) Various radiological appearances of angiomyolipomas in the same kidney. Eur Radiol 10:897-899 (Pubitemid 30353716)
54. Wong AL, McGeorge A, Clark AH (1981) Renal angiomyolipoma: a review of the literature and a report of 4 cases. Br J Urol 53:406-411 (Pubitemid 11020159)
55. Farrow GM, Harrison EG Jr, Utz DC, Jones DR (1968) Renal angiomyolipoma. A clinicopathologic study of 32 cases. Cancer 22:564-570
56. Eble JN (1998) Angiomyolipoma of kidney. Semin Diagn Pathol 15:21-40 (Pubitemid 28093786)
57. Bjornsson J, Short MP, Kwiatkowski DJ, Henske EP (1996) Tuberous sclerosis-associated renal cell carcinoma. Clinical, pathological, and genetic features. Am J Pathol 149:1201-1208 (Pubitemid 26337239)
58. Hardman JA, McNicholas TA, Kirkham N, Fletcher MS (1993) Recurrent renal angiomyolipoma associated with renal carcinoma in a patient with tuberous sclerosis. Br J Urol 72:983-984 (Pubitemid 24053537)
59. Aydin H, Magi-Galluzzi C, Lane BR, Sercia L, Lopez JL, Rini BL, Zhou M (2009) Renal angiomyolipoma: clinicopathologic study of 194 cases with emphasis on the epithelioid histology and tuberous sclerosis association. Am J Surg Pathol 33:289-297
60. Folpe AL, Mentzel T, Lehr HA, Fisher C, Balzer BL, Weiss SW (2005) Perivascular epithelioid cell neoplasms of soft tissue and gynecologic origin: a clinicopathologic study of 26 cases and review of the literature. Am J Surg Pathol 29:1558-1575
61. Jimenez RE, Eble JN, Reuter VE, Epstein JI, Folpe AL, de Peralta-Venturina M, Tamboli P, Ansell ID, Grignon DJ, Young RH, Amin MB (2001) Concurrent angiomyolipoma and renal cell neoplasia: a study of 36 cases. Mod Pathol 14:157-163 (Pubitemid 32246818)
62. Amin MB, Crotty TB, Tickoo SK, Farrow GM (1997) Renal oncocytoma: a reappraisal of morphologic features with clinicopathologic findings in 80 cases. Am J Surg Pathol 21:1-12 (Pubitemid 27026600)
63. Eble JN, Hull MT (1984) Morphologic features of renal oncocytoma: a light and electron microscopic study. Hum Pathol 15:1054-1061 (Pubitemid 15130813)
64. Zerban H, Nogueira E, Riedasch G, Bannasch P (1987) Renal oncocytoma: origin from the collecting duct. Virchows Arch B Cell Pathol Incl Mol Pathol 52:375-387 (Pubitemid 17012529)
65. Siracusano S, Zanon M, D'Aloia G, Plaino F, Trombetta C, Bussani R (1998) Rare association of renal angiomyolipoma and oncocytoma. Urology 51:837-839 (Pubitemid 28261943)
66. Al-Saleem T, Wessner LL, Scheithauer BW, Patterson K, Roach ES, Dreyer SJ, Fujikawa K, Bjornsson J, Bernstein J, Henske EP (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 83:2208-2216 (Pubitemid 28525404)
67. Breysem L, Nijs E, Proesmans W, Smet MH (2002) Tuberous sclerosis with cystic renal disease and multifocal renal cell carcinoma in a baby girl. Pediatr Radiol 32:677-680 (Pubitemid 36067717)
68. Robertson FM, Cendron M, Klauber GT, Harris BH (1996) Renal cell carcinoma in association with tuberous sclerosis in children. J Pediatr Surg 31:729-730 (Pubitemid 26152603)
69. Lane BR, Aydin H, Danforth TL, Zhou M, Remer EM, Novick AC, Campell SC (2008) Clinical correlates of renal angiomyolipoma subtypes in 209 patients: classic, fat poor, tuberous sclerosis associated and epithelioid. J Urol 180:836-843
70. Saito K, Fujii Y, Kasahara I, Kasuga T, Kihara K (2002) Malignant clear cell "sugar" tumor of the kidney: clear cell variant of epithelioid angiomyolipoma. J Urol 168:2533-2534 (Pubitemid 35402662)
71. Pea M, Bonetti F, Martignoni G, Henske EP, Manfrin E, Colato C, Bernstein J (1998) Apparent renal cell carcinomas in tuberous sclerosis are heterogeneous: the identification of malignant epithelioid angiomyolipoma. Am J Surg Pathol 22:180-187 (Pubitemid 28113378)
72. Levine AJ, Feng Z, Mak TW, You H, Jin S (2006) Coordination and communication between the p53 and IGF-1-AKT-TOR signal transduction pathways. Genes Dev 20:267-275 (Pubitemid 43200281)
73. Feng Z, Zhang H, Levine AJ, Jin S (2005) The coordinate regulation of the p53 and mTOR pathways in cells. Proc Natl Acad Sci USA 102:8204-8209 (Pubitemid 40800067)
74. Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, Birnbaum MJ, Thompson CB (2005) AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 18:283-293 (Pubitemid 41350534)
75. Nakamura T, Sakamoto K (2008) Forkhead transcription factor FOXO subfamily is essential for reactive oxygen speciesinduced apoptosis. Mol Cell Endocrinol 281:47-55 (Pubitemid 350296601)
76. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unteman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458-470
77. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonar JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN (2008) Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 358:140-151
78. Shillingford JM, Piontek KB, Germino GG, Weimbs T (2010) Rapamycin ameliorates PKD resulting from conditional inactivation of Pkd1. J Am Soc Nephrol 21:489-497
79. Carelli S, Lesma E, Paratore S, Grande V, Zadra G, Bosari S, Di Giulio AM, Gorio A (2007) Survivin expression in tuberous sclerosis complex cells. Mol Med 13:166-177 (Pubitemid 46944959)
80. Juul A, Dalgaard P, Blum WF, Bang P, Hall K, Michaelsen KF MJ, Skakkebaek NE (1995) Serum levels of insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) in healthy infants, children, and adolescents: the relation to IGF-I, IGF-II, IGFBP-1, IGFBP-2, age, sex, body mass index, and pubertal maturation. J Clin Endocrinol Metab 80:2534-2542
81. Maggio M, Ble A, Ceda GP, Metter EJ (2006) Decline in insulin-like growth factor-I levels across adult life span in two large population studies. J Gerontol A Biol Sci Med Sci 61:182-183 (Pubitemid 43334615)
82. Lesma E, Grande V, Ancona S, Carelli S, Di Giulio AM, Gorio A (2008) Anti-EGFR antibody efficiently and specifically inhibits human TSC2/ smooth muscle cell proliferation. Possible treatment options for TSC and LAM. PLoS one 3:e3558
83. Pazour GJ, Witman GB (2003) The vertebrate primary cilium is a sensory organelle. Curr Opin Cell Biol 15:105-110 (Pubitemid 36044722)
84. Yoder BK, Hou X, Guay-Woodford LM (2002) The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol 13:2508-2516
85. Hou X, Mrug M, Yoder BK, Lefkowitz EJ, Kremmidiotis G, D'Eustachio P, BeierDR Guay-Woodford LM (2002) Cystin, a novel cilia-associated protein, is disrupted in the cpk mouse model of polycystic kidney disease. J Clin Invest 109:533-540 (Pubitemid 34171785)
86. Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P (2003) Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 100:5286-5291 (Pubitemid 36542697)
87. Cardenas-Rodriguez M, Badano JL (2009) Ciliary biology: understanding the cellular and genetic basis of human ciliopathies. Am J Med Genet C Semin Med Genet 151C:263-280
88. Astrinidis A, Senapedis W, Henske EP (2006) Hamartin, the tuberous sclerosis complex 1 gene product, interacts with pololike kinase 1 in a phosphorylation-dependent manner. Hum Mol Genet 15:287-297 (Pubitemid 43125982)
89. Distefano G, Boca M, Rowe I, Wodarczyk C, Ma L, Piontek KB, Germino GG, Pandolfi PP, Boletta A (2009) 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
90. Kleymenova E, Ibraghimov-Beskrovnaya O, Kugoh H, Everitt J, Xu H, Kiguchi K, Landes G, Harris P, Walker C (2001) Tuberindependent membrane localization of polycystin-1: a functional link between polycystic kidney disease and the TSC2 tumor suppressor gene. Mol Cell 7:823-832 (Pubitemid 32436442)
91. Praetorius HA, Spring KR (2001) Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 184:71-79 (Pubitemid 33016173)
92. Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AE, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J (2003) Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 33:129-137 (Pubitemid 36177063)
93. Simons M, Gloy J, Ganner A, Bullerkotte A, Bashkurov M, Krönig C, Schermer B, Benzing T, Cabello OA, Jenny A, Mlodzik M, Polok B, Driever W, Obara T, Walz G (2005) Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37:537-543 (Pubitemid 40617284)
94. Bonnet CS, Aldred M, von Ruhland C, Harris R, Sandford R, Cheadle JP (2009) Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. Hum Mol Genet 18:2166-2176
95. Christensen ST, Pedersen LB, Schneider L, Satir P (2007) Sensory cilia and integration of signal transduction in human health and disease. Traffic 8:97-109 (Pubitemid 46099997)
96. Zhang H, Bajraszewski N, Wu E, Wang H, Moseman AP, Dabora SL, Griffin JD, Kwiatkowski DJ (2007) PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest 117:730-738 (Pubitemid 46348531)
97. Neugebauer JM, Amack JD, Peterson AG, Bisgrove BW, Yost HJ (2009) FGF signalling during embryo development regulates cilia length in diverse epithelia. Nature 458:651-654
98. Meyers EN, Martin GR (1999) Differences in left-right axis pathways in mouse and chick: functions of FGF8 and SHH. Science 285:403-406 (Pubitemid 29343961)
99. Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK (2005) Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1:e53
100. Satir P, Christensen ST (2007) Overview of structure and function of mammalian cilia. Annu Rev Physiol 69:377-400 (Pubitemid 46457649)
101. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9-22 (Pubitemid 47001784)
102. Manning BD (2004) Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J Cell Biol 167:399-403 (Pubitemid 39489047)
103. Jaeschke A, Hartkamp J, Saitoh M, Roworth W, Nobukuni T, Hodges A, Sampson J, Thomas G, Lamb R (2002) Tuberous sclerosis complex tumor suppressor-mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent. J Cell Biol 159:217-224 (Pubitemid 35283391)
104. Kwiatkowski DJ, Zhang H, Bandura JL, Heiberger KM, Glogauer M, el-Hashemite N, Onda H (2002) A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum Mol Genet 11:525-534 (Pubitemid 34257489)
105. Kenerson H, Aicher L, True L, Yeung R (2002) Activated mTOR pathway in the pathogenesis of tuberous sclerosis. In: Whittemore V (ed) New perspectives in tuberous sclerosis complex. TS Alliance, Chantilly
106. Kenerson HL, Aicher LD, True LD, Yeung RS (2002) Activated Mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res 62:5645-5650 (Pubitemid 35204715)
107. Ito N, Rubin GM (1999) Gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96:529-539 (Pubitemid 29106840)
108. Klionsky DJ, Meijer AJ, Codogno P (2005) Autophagy and p70S6 kinase. Autophagy 1:59-60, discussion 60-61
109. Noda T, Ohsumi Y (1998) Tor, a phosphatidylinositol kinase homologue, controls autophagy in yeast. J Biol Chem 273:3963-3966
110. Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ (2007) Potential therapeutic applications of autophagy. Nat Rev Drug Discov 6:304-312 (Pubitemid 46505881)
111. Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335-348 (Pubitemid 38579480)
112. Eshleman JS, Carlson BL, Mladek AC, Kastner BD, Shide KL, Sarkaria JN (2002) Inhibition of the mammalian target of rapamycin sensitizes U87 xenografts to fractionated radiation therapy. Cancer Res 62:7291-7297 (Pubitemid 36025252)
113. Paglin S, Hollister T, Delohery T, Hackett N, McMahill M, Sphicas E, Domingo D, Yahalom J (2001) A novel response of cancer cells to radiation involves autophagy and formation of acidic vesicles. Cancer Res 61:439-444 (Pubitemid 32128593)
114. Kanzawa T, Germano IM, Komata T, Ito H, Kondo Y, Kondo S (2004) Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells. Cell Death Differ 11:448-457 (Pubitemid 38489422)
115. Opipari AW Jr, Tan L, Boitano AE, Sorenson DR, Aurora A, Liu JR (2004) Resveratrol-induced autophagocytosis in ovarian cancer cells. Cancer Res 64:696-703 (Pubitemid 38120912)
116. Kondo Y, Kanzawa T, Sawaya R, Kondo S (2005) The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5:726-734 (Pubitemid 41486365)
117. Lefranc F, Kiss R (2006) Autophagy, the Trojan horse to combat glioblastomas. Neurosurg Focus 20:E7
118. Iwamaru A, Kondo Y, Iwado E, Aoki H, Fujiwara K, Yokoyama T, Mills GB, Kondo S (2007) Silencing mammalian target of rapamycin signaling by small interfering RNA enhances rapamycin-induced autophagy in malignant glioma cells. Oncogene 26:1840-1851 (Pubitemid 46474638)
119. Lefranc F, Facchini V, Kiss R (2007) Proautophagic drugs: a novel means to combat apoptosis-resistant cancers, with a special emphasis on glioblastomas. Oncologist 12:1395-1403
120. Schweichel JU, Merker HJ (1973) The morphology of various types of cell death in prenatal tissues. Teratology 7:253-266
121. Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Kianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS, Jaattela M (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 25:193-205 (Pubitemid 46109606)
122. Hoyer-Hansen M, Jaattela M (2007) Connecting endoplasmic reticulum stress to autophagy by unfolded protein response and calcium. Cell Death Differ 14:1576-1582 (Pubitemid 47278843)
123. Ozcan U, Ozcan L, Yilmaz E, Duvel K, Sahin M, Manning BD, Hotamisligil GS (2008) Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol Cell 29:541-551 (Pubitemid 351384644)