Advertisement

Tuberous Sclerosis Complex and DNA Repair

  • Samy L. Habib
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 685)

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder in humans characterized by the development of hamartomas in several organs, including renal angiomyolipomas, cardiac rhabdomyomas and subependymal giant cell astrocytomas. TSC causes disabling neurologic disorders, including epilepsy, mental retardation and autism. Brain lesions, including subependymal and subcortical hamartomas, have also been reported in TSC patients. TSC is associated with hamartomas and renal cell carcinoma (RCC) as well as sporadic tumors in TSC patient. Renal angiomyolipomas associated with TSC tend to be larger, bilateral, multifocal and present at a younger age compared with sporadic forms. Tuberous sclerosis complex of 2 genes, TSC2 encodes a protein called tuberin that normally exists in an active state and forms a heterodimeric complex with hamartin, the protein encoded by the TSC1. Deficiency of TSC2 in Eker rat is associated with the development of tumors in several organs including kidney. The majority of renal cell tumors observed in the Eker rat originates from renal proximal tubules and are histologically similar to renal cell carcinoma in humans. On the other hand, mutations in DNA repair enzyme 8-oxoG-DNA glycosylase (OGG1) are associated with cancer. OGG1 gene is found somatically mutated in some cancer cells and is highly polymorphic among human cancers. Moreover, knockout mice in OGG1 developed spontaneously adenoma and carcinoma. We recently show that the constitutive expression of OGG1 in heterozygous (TSC2+/−) Eker rat and in angiomyolipomas kidney tissue from human is 2-3fold less than in kidney from wild-type rats and control human subjects. In addition, we show that loss of TSC2 in kidney tumor of Eker rat is associated with loss of OGG1 and accumulation significant levels of oxidative DNA damage 8-oxo-deoxyguanine suggesting that TSC2 and OGG1 play a major role in renal tumorig

Keywords

Tuberous Sclerosis Tuberous Sclerosis Complex TSC2 Gene Tuberous Sclerosis Complex Patient Subependymal Giant Cell Astrocytoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Bourneville DM. Sclerose tubereuse des circonvolutions cerebrales: idiotie et epilepsie hemiplegique. Arch Neurol (Paris) 1880; 1:81–91.Google Scholar
  2. 2.
    Kandt RS, Haines JL, Smith M et al. Linkage of an important gene locus for tuberous sclerosis to a chromosome 16 marker for polycystic kidney disease. Nat Genet 1992; 2:37–41.CrossRefPubMedGoogle Scholar
  3. 3.
    Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993; 75:1305–1315.CrossRefGoogle Scholar
  4. 4.
    Van Slegtenhorst M, de Hoogt R, Hermans C et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997; 277:805–808.CrossRefPubMedGoogle Scholar
  5. 5.
    Carsillo T, Astrinidis A, Henske EP. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci USA 2000; 97:6085–6090.CrossRefPubMedGoogle Scholar
  6. 6.
    Stillwell TJ, Gomez MR, Kelalis PP. Renal lesions in tuberous sclerosis. J Urol 1987; 138:477–481.PubMedGoogle Scholar
  7. 7.
    Al-Saleem T, Wessner LL, Scheithauer BW et al. Malignant tumors of the kidney, brain and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer 1998; 83:2208–2216.CrossRefPubMedGoogle Scholar
  8. 8.
    Shapiro RA, Skinner DG, Stanley P et al. Renal tumors associated with tuberous sclerosis. the case for aggressive surgical management. J Urol 1984; 132:1170–1174.PubMedGoogle Scholar
  9. 9.
    Onda H, Lueck A, Marks PW et al. Tsc2(+/−) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. J Clin Invest 1999; 104:687–695.CrossRefPubMedGoogle Scholar
  10. 10.
    Kobayashi T, Minowa O, Kuno J et al. Renal carcinogenesis, hepatic hemangiomatosis and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 1999; 59:1206–1211.PubMedGoogle Scholar
  11. 11.
    Hino O, Mitani H, Katsuyama H et al. A novel cancer predisposition syndrome in the Eker rat model. Cancer Lett 1994; 83:117–121.CrossRefPubMedGoogle Scholar
  12. 12.
    Hino O, Klein-Szanto AJ, Freed JJ et al. Spontaneous and radiation-induced renal tumors in the Eker rat model of dominantly inherited cancer. Proc Natl Acad Sci USA 1993; 90:327–331.CrossRefPubMedGoogle Scholar
  13. 13.
    Rennebeck G, Kleymenova EV, Anderson R et al. Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryoni c lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci USA 1998; 95:15629–15634.CrossRefPubMedGoogle Scholar
  14. 14.
    Everitt JI, Goldsworthy TL, Wolf DC et al. Hereditary renal cell carcinoma in the Eker rat: A rodent familial cancer syndrome. J Urol 1992; 148:1932–1936.PubMedGoogle Scholar
  15. 15.
    Eker R, Mossige J, Johannessen JV et al. Hereditary renal adenomas and adenocarcinoma s in rats. Diagn Histopathol 1981; 4:99–110.PubMedGoogle Scholar
  16. 16.
    Everitt JI, Goldsworthy TL, Wolf DC et al. Hereditary renal cell carcinoma in the Eker rat: A unique animal model for the study of cancer susceptibility. Toxicol Lett 1995; 82–83:621–625.CrossRefPubMedGoogle Scholar
  17. 17.
    Washecka R, Hanna M. Malignant renal tumors in tuberous sclerosis. Urology 1991; 37:340–343.CrossRefPubMedGoogle Scholar
  18. 18.
    Robertson FM, Cendron M, Klauber GT et al. Renal cell carcinoma in association with tuberous sclerosis in children. J Pediatr Surg 1996; 31:729–730.CrossRefPubMedGoogle Scholar
  19. 19.
    Bjornsson J, Short MP, Kwiatkowski DJ et al. Tuberous sclerosis-associated renal cell carcinoma: clinical, pathological and genetic features. Am J Pathol 1996; 149:1201–1208.PubMedGoogle Scholar
  20. 20.
    Plank TL, Logginidou H, Klein-Szanto A et al. The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1-and TSC2-linked angiomyolipomas. Mod Pathol 1999; 12:539–545.PubMedGoogle Scholar
  21. 21.
    Habib SL. Insight into mechanism of oxidative DNA damage in angiomyolipomas from TSC patients. Mol Cancer 2009; 8:1–10.CrossRefGoogle Scholar
  22. 22.
    Johnson MW, Kerfoot C, Bushnell T et al. Hamartin and tuberin expression in human tissues. Mod Pathol 2001; 14:202–210.CrossRefPubMedGoogle Scholar
  23. 23.
    Lou D, Griffith N, Noonan DJ. The tuberous sclerosis 2 gene product can localize to nuclei in a phosphorylation-dependentmanner. Mol Cell Biol Res Commun 2001; 4:374–380.CrossRefPubMedGoogle Scholar
  24. 24.
    Lamb RF, Roy C, Diefenbach TJ et al. The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat Cell Biol 2000; 2:281–287.CrossRefPubMedGoogle Scholar
  25. 25.
    Inoki K, Li Y, Xu T et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev 2003; 17:1829–1834.CrossRefPubMedGoogle Scholar
  26. 26.
    Wienecke R, Konig A, DeClue JE. Identification of tuberin, the tuberous sclerosis-2 product. Tuberin possesses specific Rap1GAP activity. J Biol Chem 1995; 270:16409–16414.CrossRefPubMedGoogle Scholar
  27. 27.
    Jansen FE, Notenboom RG, Nellist M et al. Differential localization of hamartin and tuberin and increased S6 phosphorylation in a tuber. Neurology 2004; 63:1293–1295.PubMedGoogle Scholar
  28. 28.
    Nellist M, van Slegtenhorst MA, Goedbloed M et al. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J Biol Chem 1999; 274:35647–35652.CrossRefPubMedGoogle Scholar
  29. 29.
    van Slegtenhorst M, Nellist M, Nagelkerken B et al. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum Mol Genet 1998; 7:1053–7.CrossRefPubMedGoogle Scholar
  30. 30.
    Maheshwar MM, Cheadle JP, Jones AC et al. The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum Mol Genet 1997; 6:1991–1996.CrossRefPubMedGoogle Scholar
  31. 31.
    Nellist M, Verhaaf B, Goedbloed MA et al. TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Hum Mol Genet 2001; 10:2889–2898.CrossRefPubMedGoogle Scholar
  32. 32.
    Li Y, Inoki K, Guan KL. Biochemical and functional characterizations of small GTPase Rheb and TSC2 GAP activity. Mol Cell Biol 2004; 24:7965–7975.CrossRefPubMedGoogle Scholar
  33. 33.
    Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 1971; 68:820–823.CrossRefPubMedGoogle Scholar
  34. 34.
    Manning BD, Tee AR, Logsdon MN et al. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002; 10:151–162.CrossRefPubMedGoogle Scholar
  35. 35.
    Huang J, Manning BD. The TSC1-TSC2 complex: a molecular switchboard controlling cell growth. Biochem J 2008; 412:179–190.CrossRefPubMedGoogle Scholar
  36. 36.
    Inoki K, Li Y, Zhu T et al. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002; 4:648–657.CrossRefPubMedGoogle Scholar
  37. 37.
    Cai SL, Tee AR, Short JD et al. Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning. J Cell Biol 2006; 173:279–289.CrossRefPubMedGoogle Scholar
  38. 38.
    Xiao GH, Shoarinejad F, Jin F et al. The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J Biol Chem 1997; 272:6097–6100.CrossRefPubMedGoogle Scholar
  39. 39.
    Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003; 115:577–590.CrossRefPubMedGoogle Scholar
  40. 40.
    Ma L, Chen Z, Erdjument-Bromage H et al. Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 2005; 121:179–193.CrossRefPubMedGoogle Scholar
  41. 41.
    Ma L, Teruya-Feldstein J, Bonner P et al. Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res 2007; 67:7106–7112.CrossRefPubMedGoogle Scholar
  42. 42.
    Woods A, Johnstone SR, Dickerson K et al. LKB1 is the upstream kinase in the AMP-activated protein kinase cascade. Curr Biol 2003; 13:2004–2008.CrossRefPubMedGoogle Scholar
  43. 43.
    Shaw RJ, Kosmatka M, Bardeesy N et al. Inaugural article: The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 2004; 101:3329–3335.CrossRefPubMedGoogle Scholar
  44. 44.
    Inoki K, Li Y, Xu T et al. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes & Dev 2003; 17:1829–1834.CrossRefGoogle Scholar
  45. 45.
    Hawley SA, Boudeau J, Reid JL et al. Complexes between the LKB1 tumor suppressor, STRAD/and MO25/are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2: 28. growth by directly phosphorylating Tsc2. Nat Cell Biol 2003; 4:658–665.Google Scholar
  46. 46.
    Corradetti MN, Inoki K, Bardeesy N et al. Regulation of the TSC pathway by LKB1: Evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev 2004; 18:1533–1538.CrossRefPubMedGoogle Scholar
  47. 47.
    Sofer A, Lei K, Johannessen CM et al. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005; 25:5834–5845.CrossRefPubMedGoogle Scholar
  48. 48.
    Hara K, Maruki Y, Long X et al. Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 2002; 110:177–189.CrossRefPubMedGoogle Scholar
  49. 49.
    Oshiro N, Yoshino K, Hidayat S et al. Dissociation of raptor from mTOR is a mechanism of rapamycin-induced inhibition of mTOR function. Genes Cells 2004; 9:359–366.CrossRefPubMedGoogle Scholar
  50. 50.
    Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 2002; 110:163–175.CrossRefPubMedGoogle Scholar
  51. 51.
    Cunningham JT, Rodgers JT, Arlow DH et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007; 450:736–740.CrossRefPubMedGoogle Scholar
  52. 52.
    Jacinto E, Loewith R, Schmidt A et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 2004; 6:1122–1128.CrossRefPubMedGoogle Scholar
  53. 53.
    Robb VA, Astrinidis A, Henske EP. Frequent hyperphosphorylation of ribosomal protein S6 in lymphangioleiomyomatosis-associated angiomyolipomas. Mod Pathol 2006; 19:839–840.CrossRefPubMedGoogle Scholar
  54. 54.
    Loeb LA. Mutator phenotype may be required for multistage carcinogenesis. Cancer Res 1991; 51:3075–3079.PubMedGoogle Scholar
  55. 55.
    Chevillard S, Radicella JP, Levalois C et al. Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours. Oncogene 1998; 16:3083–3086.CrossRefPubMedGoogle Scholar
  56. 56.
    Sakumi K, Tominaga Y, Furuichi M et al. Ogg1 knockout-associated lung tumorigenesis and its suppression by Mth1 gene disruption. Cancer Res 2003; 63:902–905.PubMedGoogle Scholar
  57. 57.
    Kunisada M, Sakumi K, Tominaga Y et al. 8-Oxoguanine formation induced by chronic UVB exposure makes Ogg1 knockout mice susceptible to skin carcinogenesis. Cancer Res 2005; 65:6006–6010.CrossRefPubMedGoogle Scholar
  58. 58.
    Liao J, Seril DN, Lu GG et al. Increased susceptibility of chronic ulcerative colitis-induced carcinoma development in DNA repair enzyme Ogg1 deficient mice. Mol Carcinogenesis 2008; 47:638–646.CrossRefGoogle Scholar
  59. 59.
    Lubinski J, Hadaczek P, Podolski J et al. Common regions of deletions in chromosome regions 3p12 and 3p14.2 in primary clear cell renal carcinomas. Cancer Res 1994; 54:3710–3.PubMedGoogle Scholar
  60. 60.
    Shinmura K, Kohno T, Kasai H et al. Infrequent mutations of the hOGG1 gene, that is involved in the excision of 8-hydroxyguanine in damaged DNA, in human gastric cancer. Jpn J Cancer Res 1998; 89:825–828.PubMedGoogle Scholar
  61. 61.
    Sugimura H, Kohno T, Wakai K et al. hOGG1 Ser326Cys polymorphism and lung cancer susceptibility. Cancer Epidemiol Biomarkers Prev 1999; 8:669–674.PubMedGoogle Scholar
  62. 62.
    Audebert M, Chevillard S, Levalois C et al. Alterations of DNA repair gene OGG1 in human clear cell carcinomas of the kidney. Cancer Res 2000; 60:4740–4744.PubMedGoogle Scholar
  63. 63.
    Habib SL, Daniel E, Abboud HE et al. Genetic polymorphisms in OGG1 and their association with angiomyolipoma, a benign kidney tumor in patients with tuberous sclerosis. Cancer Biol Ther 2008; 7:23–27.CrossRefPubMedGoogle Scholar
  64. 64.
    Farinati F, Cardin R, Bortolami M et al. Oxidative DNA damage in gastric cancer: CagA status and OGG1 gene polymorphism. Int J Cancer 2008; 123:51–55.CrossRefPubMedGoogle Scholar
  65. 65.
    Jiao X, Huang J, Wu S et al. hOGG1 Ser326Cys polymorphism and susceptibility to gallbladder cancer in a Chinese population. Int J Cancer 2007; 121:501–505.CrossRefPubMedGoogle Scholar
  66. 66.
    Xing DY, Tan W, Song N et al. Ser326Cys polymorphism in hOGG1 gene and risk of esophageal cancer in a Chinese population. Int J Cancer 2001; 95:140–143.CrossRefPubMedGoogle Scholar
  67. 67.
    Elahi A, Zheng Z, Park J et al. The human OGG1 DNA repair enzyme and its association with orolaryngeal cancer risk. Carcinogenesis 2002; 23:1229–12s34.CrossRefPubMedGoogle Scholar
  68. 68.
    Habib SL, Phan MN, Patel SK et al. Reduced constitutive 8-oxoguanine-DNA glycocylase expression and impaired induction following oxidative DNA damage in the tuberin deficient Eker rat. Carcinogenesis 2003; 24:573–582.CrossRefPubMedGoogle Scholar
  69. 69.
    Habib SL, Simone S, Barnes JJ et al. Tuberin haploinsufficiency is associated with the loss of OGG1 in rat kidney tumors. Mol Cancer 2008; 7:10–14.CrossRefPubMedGoogle Scholar
  70. 70.
    Habib SL, Riley DJ, Bhandari B et al. Tuberin regulates the DNA repair enzyme OGG1. Am J Physiol Renal Physiol 2008; 294:F281–F290.CrossRefPubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2010

Authors and Affiliations

  • Samy L. Habib
    • 1
    • 2
  1. 1.South Texas Veterans Healthcare System, Geriatric Research, Education, and Clinical CenterThe University of Texas Health Science CenterSan AntonioUSA
  2. 2.Department of MedicineThe University of Texas Health Science CenterSan AntonioUSA

Personalised recommendations