The RET Protooncogene

Chapter
Part of the Cancer Treatment and Research book series (CTAR, volume 153)

Abstract

The RET protooncogene encodes a transmembrane receptor tyrosine kinase (RTK) with affinity for multiple ligands, including glial cell line-derived neurotrophic factor (GDNF). It was first described in 1985 by Takahashi and others, who identified rearrangements in the gene from human lymphoma DNA with transforming activity in a transfected cell line [1]. Over the next few years, the gene was mapped to its location on chromosome 10q11.2 [2]. RET signaling activates a number of downstream pathways implicated in cell survival and differentiation. RET knockout mice demonstrate a phenotype that includes renal agenesis and aberrant gut neurophysiology. Many effects of normal and abnormal RET proteins have been characterized in human development, physiology, and disease. Somatic mutations or rearrangements involving RET have been implicated in sporadic thyroid carcinomas. Germline activating mutations in the RET gene cause the multiple endocrine neoplasia type 2 (MEN-2) syndromes. This discovery has fundamentally changed the clinical approach and management of these patients and their at-risk family members, and provides insight into RET structure and function.

Keywords

Migration Lymphoma Codon Tyrosine Iodine 

References

  1. 1.
    Takahashi M, Ritz J, Cooper GM (1985) Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell 42:581–588PubMedCrossRefGoogle Scholar
  2. 2.
    Ishizaka Y, Itoh F, Tahira T et al (1989) Human ret proto-oncogene mapped to chromosome 10q11.2. Oncogene 4:1519–1521PubMedGoogle Scholar
  3. 3.
    Baloh RH, Tansey MG, Lampe PA et al (1998) Artemin, a novel member of the GDNF ligand family, supports peripheral and central neurons and signals through the GFRalpha3-RET receptor complex. Neuron 21:1291–1302PubMedCrossRefGoogle Scholar
  4. 4.
    Kotzbauer PT, Lampe PA, Heuckeroth RO et al (1996) Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384:467–470PubMedCrossRefGoogle Scholar
  5. 5.
    Milbrandt J, de Sauvage FJ, Fahrner TJ et al (1998) Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 20:245–253PubMedCrossRefGoogle Scholar
  6. 6.
    Treanor JJ, Goodman L, de Sauvage F et al (1996) Characterization of a multicomponent receptor for GDNF. Nature 382:80–83PubMedCrossRefGoogle Scholar
  7. 7.
    Trupp M, Arenas E, Fainzilber M et al (1996) Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381:785–789PubMedCrossRefGoogle Scholar
  8. 8.
    Runeberg-Roos P, Saarma M (2007) Neurotrophic factor receptor RET: structure, cell biology, and inherited diseases. Ann Med 39:572–580PubMedCrossRefGoogle Scholar
  9. 9.
    Jing S, Wen D, Yu Y et al (1996) GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF. Cell 85:1113–1124PubMedCrossRefGoogle Scholar
  10. 10.
    Amoresano A, Incoronato M, Monti G, Pucci P, de Franciscis V, Cerchia L (2005) Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal 17:717–727PubMedCrossRefGoogle Scholar
  11. 11.
    Kjaer S, Ibanez CF (2003) Identification of a surface for binding to the GDNF-GFR alpha 1 complex in the first cadherin-like domain of RET. J Biol Chem 278:47898–47904PubMedCrossRefGoogle Scholar
  12. 12.
    Freche B, Guillaumot P, Charmetant J et al (2005) Inducible dimerization of RET reveals a specific AKT deregulation in oncogenic signaling. J Biol Chem 280:36584–36591PubMedCrossRefGoogle Scholar
  13. 13.
    Paratcha G, Ledda F, Baars L et al (2001) Released GFRalpha1 potentiates downstream signaling, neuronal survival, and differentiation via a novel mechanism of recruitment of c-Ret to lipid rafts. Neuron 29:171–184PubMedCrossRefGoogle Scholar
  14. 14.
    Tansey MG, Baloh RH, Milbrandt J, Johnson EM Jr (2000) GFRalpha-mediated localization of RET to lipid rafts is required for effective downstream signaling, differentiation, and neuronal survival. Neuron 25:611–623PubMedCrossRefGoogle Scholar
  15. 15.
    Lucero HA, Robbins PW (2004) Lipid rafts-protein association and the regulation of protein activity. Arch Biochem Biophys 426:208–224PubMedCrossRefGoogle Scholar
  16. 16.
    Pierchala BA, Milbrandt J, Johnson EM Jr (2006) Glial cell line-derived neurotrophic factor-dependent recruitment of Ret into lipid rafts enhances signaling by partitioning Ret from proteasome-dependent degradation. J Neurosci 26:2777–2787PubMedCrossRefGoogle Scholar
  17. 17.
    Ledda F, Bieraugel O, Fard SS, Vilar M, Paratcha G (2008) Lrig1 is an endogenous inhibitor of Ret receptor tyrosine kinase activation, downstream signaling, and biological responses to GDNF. J Neurosci 28:39–49PubMedCrossRefGoogle Scholar
  18. 18.
    Donatello S, Fiorino A, Degl’Innocenti D et al (2007) SH2B1beta adaptor is a key enhancer of RET tyrosine kinase signaling. Oncogene 26:6546–6559PubMedCrossRefGoogle Scholar
  19. 19.
    Alberti L, Borrello MG, Ghizzoni S, Torriti F, Rizzetti MG, Pierotti MA (1998) Grb2 binding to the different isoforms of Ret tyrosine kinase. Oncogene 17:1079–1087PubMedCrossRefGoogle Scholar
  20. 20.
    Arighi E, Alberti L, Torriti F et al (1997) Identification of Shc docking site on Ret tyrosine kinase. Oncogene 14:773–782PubMedCrossRefGoogle Scholar
  21. 21.
    Asai N, Murakami H, Iwashita T, Takahashi M (1996) A mutation at tyrosine 1062 in MEN2A-Ret and MEN2B-Ret impairs their transforming activity and association with shc adaptor proteins. J Biol Chem 271:17644–17649PubMedCrossRefGoogle Scholar
  22. 22.
    De Vita G, Melillo RM, Carlomagno F et al (2000) Tyrosine 1062 of RET-MEN2A mediates activation of Akt (protein kinase B) and mitogen-activated protein kinase pathways leading to PC12 cell survival. Cancer Res 60:3727–3731PubMedGoogle Scholar
  23. 23.
    Degl’Innocenti D, Arighi E, Popsueva A et al (2004) Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching. Oncogene 23:7297–7309PubMedCrossRefGoogle Scholar
  24. 24.
    Encinas M, Crowder RJ, Milbrandt J, Johnson EM Jr (2004) Tyrosine 981, a novel ret autophosphorylation site, binds c-Src to mediate neuronal survival. J Biol Chem 279:18262–18269PubMedCrossRefGoogle Scholar
  25. 25.
    Hayashi H, Ichihara M, Iwashita T et al (2000) Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor. Oncogene 19:4469–4475PubMedCrossRefGoogle Scholar
  26. 26.
    Hayashi Y, Iwashita T, Murakamai H et al (2001) Activation of BMK1 via tyrosine 1062 in RET by GDNF and MEN2A mutation. Biochem Biophys Res Commun 281:682–689PubMedCrossRefGoogle Scholar
  27. 27.
    Iwashita T, Asai N, Murakami H, Matsuyama M, Takahashi M (1996) Identification of tyrosine residues that are essential for transforming activity of the ret proto-oncogene with MEN2A or MEN2B mutation. Oncogene 12:481–487PubMedGoogle Scholar
  28. 28.
    Kurokawa K, Iwashita T, Murakami H, Hayashi H, Kawai K, Takahashi M (2001) Identification of SNT/FRS2 docking site on RET receptor tyrosine kinase and its role for signal transduction. Oncogene 20:1929–1938PubMedCrossRefGoogle Scholar
  29. 29.
    Lopez-Ramirez MA, Dominguez-Monzon G, Vergara P, Segovia J (2008) Gas1 reduces Ret tyrosine 1062 phosphorylation and alters GDNF-mediated intracellular signaling. Int J Dev Neurosci 26:497–503PubMedCrossRefGoogle Scholar
  30. 30.
    Pandey A, Duan H, Di Fiore PP, Dixit VM (1995) The Ret receptor protein tyrosine kinase associates with the SH2-containing adapter protein Grb10. J Biol Chem 270:21461–21463PubMedCrossRefGoogle Scholar
  31. 31.
    Pandey A, Liu X, Dixon JE, Di Fiore PP, Dixit VM (1996) Direct association between the Ret receptor tyrosine kinase and the Src homology 2-containing adapter protein Grb7. J Biol Chem 271:10607–10610PubMedCrossRefGoogle Scholar
  32. 32.
    Salvatore D, Barone MV, Salvatore G et al (2000) Tyrosines 1015 and 1062 are in vivo autophosphorylation sites in ret and ret-derived oncoproteins. J Clin Endocrinol Metab 85:3898–3907PubMedCrossRefGoogle Scholar
  33. 33.
    Wong A, Bogni S, Kotka P et al (2005) Phosphotyrosine 1062 is critical for the in vivo activity of the Ret9 receptor tyrosine kinase isoform. Mol Cell Biol 25:9661–9673PubMedCrossRefGoogle Scholar
  34. 34.
    Coulpier M, Anders J, Ibanez CF (2002) Coordinated activation of autophosphorylation sites in the RET receptor tyrosine kinase: importance of tyrosine 1062 for GDNF mediated neuronal differentiation and survival. J Biol Chem 277:1991–1999PubMedCrossRefGoogle Scholar
  35. 35.
    Kawamoto Y, Takeda K, Okuno Y et al (2004) Identification of RET autophosphorylation sites by mass spectrometry. J Biol Chem 279:14213–14224PubMedCrossRefGoogle Scholar
  36. 36.
    Arighi E, Borrello MG, Sariola H (2005) RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev 16:441–467PubMedCrossRefGoogle Scholar
  37. 37.
    Trupp M, Scott R, Whittemore SR, Ibanez CF (1999) Ret-dependent and -independent mechanisms of glial cell line-derived neurotrophic factor signaling in neuronal cells. J Biol Chem 274:20885–20894PubMedCrossRefGoogle Scholar
  38. 38.
    van Weering DH, Medema JP, van Puijenbroek A, Burgering BM, Baas PD, Bos JL (1995) Ret receptor tyrosine kinase activates extracellular signal-regulated kinase 2 in SK-N-MC cells. Oncogene 11:2207–2214PubMedGoogle Scholar
  39. 39.
    Borrello MG, Alberti L, Arighi E et al (1996) The full oncogenic activity of Ret/ptc2 depends on tyrosine 539, a docking site for phospholipase Cgamma. Mol Cell Biol 16:2151–2163PubMedGoogle Scholar
  40. 40.
    Chiariello M, Visconti R, Carlomagno F et al (1998) Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKS): evidence for a divergence of the ERKs and JNKs pathways induced by Ret. Oncogene 16:2435–2445PubMedCrossRefGoogle Scholar
  41. 41.
    Fukuda T, Kiuchi K, Takahashi M (2002) Novel mechanism of regulation of Rac activity and lamellipodia formation by RET tyrosine kinase. J Biol Chem 277:19114–19121PubMedCrossRefGoogle Scholar
  42. 42.
    Asai N, Fukuda T, Wu Z et al (2006) Targeted mutation of serine 697 in the Ret tyrosine kinase causes migration defect of enteric neural crest cells. Development 133:4507–4516PubMedCrossRefGoogle Scholar
  43. 43.
    Lee RH, Wong WL, Chan CH, Chan SY (2006) Differential effects of glial cell line-derived neurotrophic factor and neurturin in RET/GFRalpha1-expressing cells. J Neurosci Res 83:80–90PubMedCrossRefGoogle Scholar
  44. 44.
    Parkash V, Leppanen VM, Virtanen H et al (2008) The structure of the glial cell line-derived neurotrophic factor-coreceptor complex: insights into RET signaling and heparin binding. J Biol Chem 283:35164–35172PubMedCrossRefGoogle Scholar
  45. 45.
    Borrello MG, Mercalli E, Perego C et al (2002) Differential interaction of Enigma protein with the two RET isoforms. Biochem Biophys Res Commun 296:515–522PubMedCrossRefGoogle Scholar
  46. 46.
    Tsui-Pierchala BA, Ahrens RC, Crowder RJ, Milbrandt J, Johnson EM Jr (2002) The long and short isoforms of Ret function as independent signaling complexes. J Biol Chem 277:34618–34625PubMedCrossRefGoogle Scholar
  47. 47.
    Schuetz G, Rosario M, Grimm J, Boeckers TM, Gundelfinger ED, Birchmeier W (2004) The neuronal scaffold protein Shank3 mediates signaling and biological function of the receptor tyrosine kinase Ret in epithelial cells. J Cell Biol 167:945–952PubMedCrossRefGoogle Scholar
  48. 48.
    Schuchardt A, D’Agati V, Larsson-Blomberg L, Costantini F, Pachnis V (1994) Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367:380–383PubMedCrossRefGoogle Scholar
  49. 49.
    de Graaff E, Srinivas S, Kilkenny C et al (2001) Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 15:2433–2444PubMedCrossRefGoogle Scholar
  50. 50.
    Srinivas S, Wu Z, Chen CM, D’Agati V, Costantini F (1999) Dominant effects of RET receptor misexpression and ligand-independent RET signaling on ureteric bud development. Development 126:1375–1386PubMedGoogle Scholar
  51. 51.
    Lee DC, Chan KW, Chan SY (2002) RET receptor tyrosine kinase isoforms in kidney function and disease. Oncogene 21:5582–5592PubMedCrossRefGoogle Scholar
  52. 52.
    Pichel JG, Shen L, Sheng HZ et al (1996) Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382:73–76PubMedCrossRefGoogle Scholar
  53. 53.
    Schuchardt A, D’Agati V, Pachnis V, Costantini F (1996) Renal agenesis and hypodysplasia in ret-k- mutant mice result from defects in ureteric bud development. Development 122:1919–1929PubMedGoogle Scholar
  54. 54.
    Enomoto H, Araki T, Jackman A et al (1998) GFR alpha1-deficient mice have deficits in the enteric nervous system and kidneys. Neuron 21:317–324PubMedCrossRefGoogle Scholar
  55. 55.
    Enomoto H, Heuckeroth RO, Golden JP, Johnson EM, Milbrandt J (2000) Development of cranial parasympathetic ganglia requires sequential actions of GDNF and neurturin. Development 127:4877–4889PubMedGoogle Scholar
  56. 56.
    Taraviras S, Marcos-Gutierrez CV, Durbec P et al (1999) Signalling by the RET receptor tyrosine kinase and its role in the development of the mammalian enteric nervous system. Development 126:2785–2797PubMedGoogle Scholar
  57. 57.
    Veiga-Fernandes H, Coles MC, Foster KE et al (2007) Tyrosine kinase receptor RET is a key regulator of Peyer’s patch organogenesis. Nature 446:547–551PubMedCrossRefGoogle Scholar
  58. 58.
    Marcos C, Pachnis V (1996) The effect of the ret- mutation on the normal development of the central and parasympathetic nervous systems. Int J Dev Biol Suppl. 1:137S–138SPubMedGoogle Scholar
  59. 59.
    Donis-Keller H, Dou S, Chi D et al (1993) Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet 2:851–856PubMedCrossRefGoogle Scholar
  60. 60.
    Mulligan LM, Kwok JB, Healey CS et al (1993) Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature 363:458–460PubMedCrossRefGoogle Scholar
  61. 61.
    Carlson KM, Dou S, Chi D et al (1994) Single missense mutation in the tyrosine kinase catalytic domain of the RET protooncogene is associated with multiple endocrine neoplasia type 2B. Proc Natl Acad Sci USA 91:1579–1583PubMedCrossRefGoogle Scholar
  62. 62.
    Brandi ML, Gagel RF, Angeli A et al (2001) Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 86:5658–5671PubMedCrossRefGoogle Scholar
  63. 63.
    Miller CA, Ellison EC (2005) Multiple Endocrine Neoplasia Type 2B. In: Clark OH, Duh Q-Y, Kebebew E (eds) Textbook of endocrine surgery, 2nd edn. W.B. Saunders, Philadelphia, pp 757–763Google Scholar
  64. 64.
    Eng C, Clayton D, Schuffenecker I et al (1996) The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 276:1575–1579PubMedCrossRefGoogle Scholar
  65. 65.
    Frank-Raue K, Hoppner W, Frilling A et al (1996) Mutations of the ret protooncogene in German multiple endocrine neoplasia families: relation between genotype and phenotype. German medullary thyroid carcinoma study group. J Clin Endocrinol Metab 81:1780–1783PubMedCrossRefGoogle Scholar
  66. 66.
    Quayle FJ, Fialkowski EA, Benveniste R, Moley JF (2007) Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery 142:800–805 Discussion 5 e1PubMedCrossRefGoogle Scholar
  67. 67.
    Rodriguez JM, Balsalobre M, Ponce JL et al (2008) Pheochromocytoma in MEN 2A syndrome. Study of 54 patients. World J Surg 32:2520–2526PubMedCrossRefGoogle Scholar
  68. 68.
    Machens A, Brauckhoff M, Holzhausen HJ, Thanh PN, Lehnert H, Dralle H (2005) Codon-specific development of pheochromocytoma in multiple endocrine neoplasia type 2. J Clin Endocrinol Metab 90:3999–4003PubMedCrossRefGoogle Scholar
  69. 69.
    Howe JR, Norton JA, Wells SA Jr (1993) Prevalence of pheochromocytoma and hyperparathyroidism in multiple endocrine neoplasia type 2A: results of long-term follow-up. Surgery 114:1070–1077PubMedGoogle Scholar
  70. 70.
    Kraimps JL, Denizot A, Carnaille B et al (1996) Primary hyperparathyroidism in multiple endocrine neoplasia type IIa: retrospective French multicentric study. Groupe d’Etude des Tumeurs a Calcitonine (GETC, French Calcitonin Tumors Study Group), French Association of Endocrine Surgeons. World J Surg 20:808–812 Discussion 12–13PubMedCrossRefGoogle Scholar
  71. 71.
    Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr, Lairmore TC (1996) Surgical management of hyperparathyroidism in patients with multiple endocrine neoplasia type 2A. Surgery 120:966–973 Discussion 73–74PubMedCrossRefGoogle Scholar
  72. 72.
    Schuffenecker I, Virally-Monod M, Brohet R et al (1998) Risk and penetrance of primary hyperparathyroidism in multiple endocrine neoplasia type 2A families with mutations at codon 634 of the RET proto-oncogene. Groupe D’etude des Tumeurs a Calcitonine. J Clin Endocrinol Metab 83:487–491PubMedCrossRefGoogle Scholar
  73. 73.
    Miyauchi A, Futami H, Hai N et al (1999) Two germline missense mutations at codons 804 and 806 of the RET proto-oncogene in the same allele in a patient with multiple endocrine neoplasia type 2B without codon 918 mutation. Jpn J Cancer Res 90:1–5PubMedGoogle Scholar
  74. 74.
    Gujral TS, Singh VK, Jia Z, Mulligan LM (2006) Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2B. Cancer Res 66:10741–10749PubMedCrossRefGoogle Scholar
  75. 75.
    Santoro M, Carlomagno F, Romano A et al (1995) Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science 267:381–383PubMedCrossRefGoogle Scholar
  76. 76.
    Bongarzone I, Vigano E, Alberti L et al (1998) Full activation of MEN2B mutant RET by an additional MEN2A mutation or by ligand GDNF stimulation. Oncogene 16:2295–2301PubMedCrossRefGoogle Scholar
  77. 77.
    Songyang Z, Carraway KL 3rd, Eck MJ et al (1995) Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. Nature 373:536–539PubMedCrossRefGoogle Scholar
  78. 78.
    Bocciardi R, Mograbi B, Pasini B et al (1997) The multiple endocrine neoplasia type 2B point mutation switches the specificity of the Ret tyrosine kinase towards cellular substrates that are susceptible to interact with Crk and Nck. Oncogene 15:2257–2265PubMedCrossRefGoogle Scholar
  79. 79.
    Liu X, Vega QC, Decker RA, Pandey A, Worby CA, Dixon JE (1996) Oncogenic RET receptors display different autophosphorylation sites and substrate binding specificities. J Biol Chem 271:5309–5312PubMedCrossRefGoogle Scholar
  80. 80.
    Murakami H, Iwashita T, Asai N et al (1999) Enhanced phosphatidylinositol 3-kinase activity and high phosphorylation state of its downstream signalling molecules mediated by ret with the MEN 2B mutation. Biochem Biophys Res Commun 262:68–75PubMedCrossRefGoogle Scholar
  81. 81.
    Asai N, Iwashita T, Matsuyama M, Takahashi M (1995) Mechanism of activation of the ret proto-oncogene by multiple endocrine neoplasia 2A mutations. Mol Cell Biol 15:1613–1619PubMedGoogle Scholar
  82. 82.
    Kjaer S, Kurokawa K, Perrinjaquet M, Abrescia C, Ibanez CF (2006) Self-association of the transmembrane domain of RET underlies oncogenic activation by MEN2A mutations. Oncogene 25:7086–7095PubMedCrossRefGoogle Scholar
  83. 83.
    D’Aloiso L, Carlomagno F, Bisceglia M et al (2006) Clinical case seminar: in vivo and in vitro characterization of a novel germline RET mutation associated with low-penetrant nonaggressive familial medullary thyroid carcinoma. J Clin Endocrinol Metab 91:754–759PubMedCrossRefGoogle Scholar
  84. 84.
    Jimenez C, Dang GT, Schultz PN et al (2004) A novel point mutation of the RET protooncogene involving the second intracellular tyrosine kinase domain in a family with medullary thyroid carcinoma. J Clin Endocrinol Metab 89:3521–3526PubMedCrossRefGoogle Scholar
  85. 85.
    Pigny P, Bauters C, Wemeau JL et al (1999) A novel 9-base pair duplication in RET exon 8 in familial medullary thyroid carcinoma. J Clin Endocrinol Metab 84:1700–1704PubMedCrossRefGoogle Scholar
  86. 86.
    Ercolino T, Lombardi A, Becherini L et al (2008) The Y606C RET mutation causes a receptor gain of function. Clin Endocrinol (Oxf) 69:253–258CrossRefGoogle Scholar
  87. 87.
    Machens A, Dralle H (2007) Genotype-phenotype based surgical concept of hereditary medullary thyroid carcinoma. World J Surg 31:957–968PubMedCrossRefGoogle Scholar
  88. 88.
    Elisei R, Cosci B, Romei C et al (2008) Prognostic significance of somatic RET oncogene mutations in sporadic medullary thyroid cancer: a 10-year follow-up study. J Clin Endocrinol Metab 93:682–687PubMedCrossRefGoogle Scholar
  89. 89.
    Marsh DJ, Learoyd DL, Andrew SD et al (1996) Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma. Clin Endocrinol (Oxf) 44:249–257CrossRefGoogle Scholar
  90. 90.
    Zedenius J, Larsson C, Bergholm U et al (1995) Mutations of codon 918 in the RET proto-oncogene correlate to poor prognosis in sporadic medullary thyroid carcinomas. J Clin Endocrinol Metab 80:3088–3090PubMedCrossRefGoogle Scholar
  91. 91.
    Schilling T, Burck J, Sinn HP et al (2001) Prognostic value of codon 918 (ATG– > ACG) RET proto-oncogene mutations in sporadic medullary thyroid carcinoma. Int J Cancer 95:62–66PubMedCrossRefGoogle Scholar
  92. 92.
    Eng C, Mulligan LM, Healey CS et al (1996) Heterogeneous mutation of the RET proto-oncogene in subpopulations of medullary thyroid carcinoma. Cancer Res 56:2167–2170PubMedGoogle Scholar
  93. 93.
    Ciampi R, Giordano TJ, Wikenheiser-Brokamp K, Koenig RJ, Nikiforov YE (2007) HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer 14:445–452PubMedCrossRefGoogle Scholar
  94. 94.
    Santoro M, Melillo RM, Fusco A (2006) RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur J Endocrinol 155:645–653PubMedCrossRefGoogle Scholar
  95. 95.
    Zhu Z, Ciampi R, Nikiforova MN, Gandhi M, Nikiforov YE (2006) Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity. J Clin Endocrinol Metab 91:3603–3610PubMedCrossRefGoogle Scholar
  96. 96.
    Bounacer A, Wicker R, Caillou B et al (1997) High prevalence of activating ret proto-oncogene rearrangements, in thyroid tumors from patients who had received external radiation. Oncogene 15:1263–1273PubMedCrossRefGoogle Scholar
  97. 97.
    Collins BJ, Chiappetta G, Schneider AB et al (2002) RET expression in papillary thyroid cancer from patients irradiated in childhood for benign conditions. J Clin Endocrinol Metab 87:3941–3946PubMedCrossRefGoogle Scholar
  98. 98.
    Fugazzola L, Pilotti S, Pinchera A et al (1995) Oncogenic rearrangements of the RET proto-oncogene in papillary thyroid carcinomas from children exposed to the Chernobyl nuclear accident. Cancer Res 55:5617–5620PubMedGoogle Scholar
  99. 99.
    Ito T, Seyama T, Iwamoto KS et al (1994) Activated RET oncogene in thyroid cancers of children from areas contaminated by Chernobyl accident. Lancet 344:259PubMedGoogle Scholar
  100. 100.
    Klugbauer S, Jauch A, Lengfelder E, Demidchik E, Rabes HM (2000) A novel type of RET rearrangement (PTC8) in childhood papillary thyroid carcinomas and characterization of the involved gene (RFG8). Cancer Res 60:7028–7032PubMedGoogle Scholar
  101. 101.
    Nikiforov YE, Rowland JM, Bove KE, Monforte-Munoz H, Fagin JA (1997) Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 57:1690–1694PubMedGoogle Scholar
  102. 102.
    Rabes HM, Demidchik EP, Sidorow JD et al (2000) Pattern of radiation-induced RET and NTRK1 rearrangements in 191 post-chernobyl papillary thyroid carcinomas: biological, phenotypic, and clinical implications. Clin Cancer Res 6:1093–1103PubMedGoogle Scholar
  103. 103.
    Alipov G, Ito M, Prouglo Y, Takamura N, Yamashita S (1999) Ret proto-oncogene rearrangement in thyroid cancer around Semipalatinsk nuclear testing site. Lancet 354:1528–1529PubMedCrossRefGoogle Scholar
  104. 104.
    Thomas GA, Bunnell H, Cook HA et al (1999) High prevalence of RET/PTC rearrangements in Ukrainian and Belarussian post-Chernobyl thyroid papillary carcinomas: a strong correlation between RET/PTC3 and the solid-follicular variant. J Clin Endocrinol Metab 84:4232–4238PubMedCrossRefGoogle Scholar
  105. 105.
    Ito T, Seyama T, Iwamoto KS et al (1993) In vitro irradiation is able to cause RET oncogene rearrangement. Cancer Res 53:2940–2943PubMedGoogle Scholar
  106. 106.
    Mizuno T, Iwamoto KS, Kyoizumi S et al (2000) Preferential induction of RET/PTC1 rearrangement by X-ray irradiation. Oncogene 19:438–443PubMedCrossRefGoogle Scholar
  107. 107.
    Mizuno T, Kyoizumi S, Suzuki T, Iwamoto KS, Seyama T (1997) Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene 15:1455–1460PubMedCrossRefGoogle Scholar
  108. 108.
    Fischer AH, Bond JA, Taysavang P, Battles OE, Wynford-Thomas D (1998) Papillary thyroid carcinoma oncogene (RET/PTC) alters the nuclear envelope and chromatin structure. Am J Pathol 153:1443–1450PubMedGoogle Scholar
  109. 109.
    Carlomagno F, Anaganti S, Guida T et al (2006) BAY 43–9006 inhibition of oncogenic RET mutants. J Natl Cancer Inst 98:326–334PubMedCrossRefGoogle Scholar
  110. 110.
    Carlomagno F, Vitagliano D, Guida T et al (2002) ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62:7284–7290PubMedGoogle Scholar
  111. 111.
    Cohen MS, Hussain HB, Moley JF (2002) Inhibition of medullary thyroid carcinoma cell proliferation and RET phosphorylation by tyrosine kinase inhibitors. Surgery 132:960–966 Discussion 6–7PubMedCrossRefGoogle Scholar
  112. 112.
    de Groot JW, Plaza Menacho I, Schepers H et al (2006) Cellular effects of imatinib on medullary thyroid cancer cells harboring multiple endocrine neoplasia Type 2A and 2B associated RET mutations. Surgery 139:806–814PubMedCrossRefGoogle Scholar
  113. 113.
    Kim DW, Jo YS, Jung HS et al (2006) An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab 91:4070–4076PubMedCrossRefGoogle Scholar
  114. 114.
    Marsee DK, Venkateswaran A, Tao H et al (2004) Inhibition of heat shock protein 90, a novel RET/PTC1-associated protein, increases radioiodide accumulation in thyroid cells. J Biol Chem 279:43990–43997PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Endocrine and Oncologic Surgery SectionSiteman Cancer Center, Washington University School of MedicineSt. LouisUSA

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