Abstract
Multiple endocrine neoplasia type 2B (MEN 2B) is a familial cancer syndrome, in which the cardinal feature is medullary thyroid carcinoma (MTC), a malignant tumor arising from the calcitonin producing thyroid C-cells. MEN 2B is associated with a germline point mutation in the RET proto-oncogene, leading to a Met→Thr substitution at codon 918 in the kinase domain, which alters the substrate specificity of the protein. We used the human calcitonin gene (CALC-I) promoter to generate transgenic mice expressing either the human RET oncogene with the MEN2B-specific 918 Met→Thr mutation (CALC-MEN2B-RET) or the human non-mutated RET proto-oncogene (CALC-WT-RET) in the C-cells. At 20–22 months of age three out of eight CALC-MEN2B-RET transgenic founders presented with macroscopic bilateral MTC. In two founders nodular C-cell hyperplasia (CCH) was observed. Thyroid abnormalities were never observed in CALC-WT-RET transgenic mice or control non-transgenic mice analysed at this age. In some mice from established CALC-MEN2B-RET transgenic lines nodular CCH was observed from 8 months on whereas MTC was detected in 13% of mice from one CALC-MEN2B-RET line, from the age of 11 months on. These results show for the first time that the MEN2B mutation in the RET oncogene predisposes mice for MTC.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Asai N, Iwashita T, Matsuyama M and Takahashi M. . 1995 Mol. Cell. Biol. 15: 1613–1619.
Carlson KM, Dou S, Chi D, Scavarda N, Jackson CE, Wells Jr SA, Goodfellow PJ and Donis-Keller H. . 1994 Proc. Natl. Acad. Sci. 9: 1579–1583.
Carney JA, Sizemore GW and Lovestedt SA. . 1976 Oral Surg. Oral Med. Oral Pathol. 41: 793–795.
Coxon AB, Ward JM, Gerardts J, Otterson GA, Zajac-Kaye M and Kaye JF. . 1998 Oncogene 17: 1625–1628.
Donis-Keller H, Dou S, Chi D, Carlson KM, Toshima K, Lairmore TC, Howe JR, Moley JF, Goodfellow PJ and Wells SA. . 1993 Hum. Mol. Genet. 2: 1579–1583.
Eng C, Smith DP, Mulligan LM, Nagai MA, Healey CS, Ponder MA, Gardner E, Scheuman GFW, Jackson CE, Tunnacliffe A and Ponder BAJ. . 1994 Hum. Mol. Genet. 3: 237–241.
Hofstra RMW, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B, Höppener JWM, Ploos van Amstel JK, Romeo G, Lips CJM and Buys CHCM. . 1994 Nature 367: 375–376.
Horn Jr RC. . 1951 Cancer 4: 697.
Landsvater RM, de Wit MJ, Zewald RA, Hofstra RM, Buys CH, Ploos van Amstel HK, Höppener JW and Lips CJ. . 1996 Cancer Res. 56: 4853–4855.
Lips CJM, Landsvater RM, Höppener JWM, Geerdink RA, Blijham G, Jansen-Schilhorn van Veen JMJ, van Gils APG, de Wit MJ, Zewald RA, Berends MJH, Breemer FA, Brouwers-Smalbraak J, Jansen RPM, Ploos van Amstel HK, Van Vroonhoven TJMV and Vroom TM. . 1994 N. Engl. J. Med. 331: 828–835.
Marsh DJ, Andrew SD, Eng C, Learoyd DI, Capes AG, Pojer R, Richardson AL, Houghton C, Mulligan LM, Ponder BA and Robinson BG. . 1996 Cancer Res. 56: 1241–1243.
Michiels FM, Chappuis S, Caillou B, Passini A, Talbot M, Monier R, Lenoir GM, Feunteun J and Billaud M. . 1997 Proc. Natl. Acad. Sci. 94: 3330–3335.
Mulligan LM, Kwok JBJ, Healey CS, Elsdon MJ, Eng C, Gardner E, Love DR, Mole SE, Moore JK, Papi L, Ponder MA, Thelenius H, Tunnacliffe A and Ponder BAJ. . 1993 Nature 363: 458–460.
Myers SM, Eng C, Ponder BA and Mulligan LM. . 1996 Oncogene 11: 2039–2045.
Steiner AL, Goodman AD and Powers SR. . 1968 Medicine 47: 371–409.
Santoro M, Carlomagno F, Romano A, Bottaro DP, Dathan NA, Grieco M, Fusco A, Vecchio G, Matoskova B, Kaus MH and Di Fior R. . 1995 Science 267: 381–383.
Schuchardt A, D'Agati V, Larson-Blomberg L, Constantini F and Pachnis V. . 1994 Nature 367: 380–383.
Sipple JH. . 1961 Am. J. Med. 31: 163–166.
Smith-Hicks CL, Sizer KC, Powers JF, Tishler AS and Constantini F. . 2000 EMBO J. 19: 612–622.
Sweetser DA, Froelick GJ, Matsumoto AM, Kafer KE, Marck B, Palmitter RD and Kapur RP. . 1999 Oncogene 18: 877–886.
Tahira T, Ishizaka Y, Itoh F, Sugimura T and Nagao M. . 1990 Oncogene 3: 97–102.
Takahashi M, Buma Y, Iwamoto T, Inagumo Y, Ikeda H and Hiai H. . 1988 Oncogene 3: 571–578.
Trupp M, Arenas E, Feinzilber M, Nilson A-S, Sieber B-A, Grigoriou M, Kilkenny C, Salazar-Grueso E, Pachnis V, Arumae U, Sariola H, Saarma M and Ibanez CF. . 1996 Nature 381: 785–789.
Acknowledgements
The authors would like to thank Prof Dr JL Bos for providing the human RET cDNA and Prof Dr Th M Vroom for evaluation of thyroid pathology. This work was supported by a grant from the Dutch Cancer Society (KWF) and a grant from the UMCU ‘Genvlag-project’.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Acton, D., Velthuyzen, D., Lips, C. et al. Multiple endocrine neoplasia type 2B mutation in human RET oncogene induces medullary thyroid carcinoma in transgenic mice. Oncogene 19, 3121–3125 (2000). https://doi.org/10.1038/sj.onc.1203648
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.onc.1203648
Keywords
This article is cited by
-
Genetically engineered mouse models of head and neck cancers
Oncogene (2023)
-
Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes
Nature Reviews Clinical Oncology (2018)
-
Classical point mutations of RET, BRAF and RAS oncogenes are not shared in papillary and medullary thyroid cancer occurring simultaneously in the same gland
Journal of Endocrinological Investigation (2017)
-
Medullary Thyroid Carcinoma: a 25-Year Perspective
Endocrine Pathology (2014)
-
Sprouty1 is a candidate tumor-suppressor gene in medullary thyroid carcinoma
Oncogene (2012)