Abstract
The cyclic AMP pathway is a major regulator of thyrocyte function and proliferation and, predictably, its inappropriate activation is associated with a sub-set of human thyroid tumours. Activating mutations are, however, more common in the thyrotropin receptor (TSHR) than in its downstream transducer, Gαs. To investigate whether this reflects an inherent difference in their oncogenic potency, we compared the effects of retrovirally-transduced mutant (A623I) TSHR or (Q227L) Gαs (GSP), using the rat thyroid cell line FRTL5 and primary human thyrocytes. In FRTL5, expression of GSP or mutant (m) TSHR induced a 2 – 3-fold increase in basal levels of cAMP. This was associated with TSH-independent proliferation (assessed by both cell number and DNA synthesis) and function (as shown by increased expression of thyroglobulin (Tg) and the sodium/iodide symporter). In primary cultures, expression of mTSHR, but not GSP, consistently induced formation of colonies with epithelial morphology and thyroglobulin expression, capable of 10 – 15 population doublings (PD) compared to less than three in controls. Thus, while mTSHR and GSP exert similar effects in FRTL5, use of primary cultures reveals a major difference in their ability to induce sustained proliferation in normal human thyrocytes, and provides the first direct evidence that mTSHR is sufficient to initiate thyroid tumorigenesis.
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References
Ajjan R, Watson P, Findlay C, Metcalfe A, Crisp M, Ludgate M and Weetman A. . 1998 J. Endocrinol. 158: 351–358.
Bond JA, Wyllie FS, Rowson J, Radulescu A and Wynford-Thomas D. . 1994 Oncogene 9: 281–290.
Burns JS, Shaw J, Williams ED and Wynford-Thomas D. . 1992 Int. J. Oncol. 1: 79–92.
Chomczynski P and Sacchi N. . 1987 Analyt. Biochem. 162: 156–159.
Costagliola S, Many M-C, Stalmans-Falys M, Tonacchera M, Vassart G and Ludgate M. . 1994 Endocrinol. 135: 2150–2159.
Dai G, Levy O and Carrasco N. . 1996 Nature 379: 458–460.
Danos O and Mulligan RC. . 1988 Proc. Natl. Acad. Sci. USA 85: 6460–6464.
Dumont JE, Lamy F, Roger P and Maenhaut C. . 1992 Phys. Rev. 72: 667–697.
Duprez L, Parma J, Van Sande J, Allgeier A, Leclere J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J and Vassart G. . 1994 Nature Genet. 7: 396–401.
Fournes B, Monier R, Michiels F, Milgrom E, Misrahi M and Feunteun J. . 1998 Oncogene 16: 985–990.
Fuhrer D, Holzapfee H, Wonerow P, Scherbaum W and Paschke R. . 1997 J. Clin. Endocrinol. Metab. 82: 3885–3891.
Ivan M, Ludgate M, Gire V, Bond JA and Wynford-Thomas D. . 1997 J. Clin. Endocrinol. Metab. 82: 2702–2709.
Kupperman E, Wen W and Meinkoth JL. . 1993 Mol. Cell. Biol. 13: 4477–4484.
Lalli E and Sassonecorsi P. . 1995 Proc. Natl. Acad. Sci. USA 92: 9633–9637.
Michiels F, Caillou B, Talbot M, Dessarps-Freichey F, Maunoury M, Schlumberger M, Merken L and Monier R. . 1994 Proc. Natl. Acad. Sci. USA 91: 10488–10492.
Muca C and Vallar L. . 1994 Oncogene 9: 3647–3653.
Nemoz G, Sette C, Hess M, Muca C, Vallar L and Conti M. . 1995 Mol. Endocrinol. 9: 1279–1287.
O'Sullivan C, Barton CM, Staddon SL, Brown CL and Lemoine NR. . 1991 Mol. Carcinogen. 4: 345–349.
Parma J, Duprez L, Van Sande J, Cochaux P, Gervy C, Mockel J, Dumont J and Vassart G. . 1993 Nature 365: 649–651.
Parma J, Duprez L, Van Sande J, Hermans J, Rocmans P and VanVliet G. . 1997 J. Clin. Endocrinol. Metab. 82: 2695–2701.
Parma J, Van Sande J, Swillens S, Tonacchera M, Dumont JE and Vassart G. . 1995 Mol. Endocrinol. 9: 725–733.
Paschke R and Ludgate M. . 1997 New Engl. J. Med. 337: 1675–1681.
Paschke R, Tonacchera M, Van Sande J, Parma J and Vassart G. . 1994 J. Clin. Endocrinol. Metab. 79: 1785–1789.
Porcellini A, Ruggiano G, Pannain S, Ciullo I, Amabile G, Fenzi G and Avvedimento EV. . 1997 Oncogene 15: 781–789.
Rapoport B, Filetti S, Takai N and Seto P. . 1982 FEBS Letts 146: 23–27.
Russo D, Arturi F, Schlumberger M, Caillou B, Monier R, Filetti S and Suarez HG. . 1995a Oncogene 11: 1907–1911.
Russo D, Arturi F, Suarez H, Schlumberger M, DuVillard JA, Crocetti U and Filetti S. . 1996 J. Clin. Endocrinol. Metab. 81: 1548–1551.
Russo D, Arturi F, Wicker R, Chazenbalk GD, Schlumberger M, DuVillard J-AD, Caillou B, Monier R, Rapoport B, Filetti S and Suarez HG. . 1995b J. Clin. Endocrinol. Metab. 80: 1347–1351.
Said S, Schlumberger M and Suarez HG. . 1994 J. Endocrinol. Invest. 17: 371–379.
Van Biesen T, Luttrell LM, Hawes BE and Lefkowitz RJ. . 1996 Endocrine Rev. 17: 698–709.
Van Sande J, Parma J, Tonacchera M, Swillens S, Dumont J and Vassart G. . 1995 J. Clin. Endocrinol. Metab. 80: 2577–2585.
Vassart G and Dumont JE. . 1992 Endocrine Rev. 13: 596–611.
Williams DW, Williams ED and Wynford-Thomas D. . 1988 Br. J. Cancer 57: 535–539.
Wynford-Thomas D. . 1993 Cancer Surveys 16: 115–133.
Wynford-Thomas D. . 1997a Eur. J. Cancer 33: 716–726.
Wynford-Thomas D. . 1997b Hormone Res. 47: 145–157.
Wynford-Thomas D, Stringer BMJ and Williams ED. . 1982 Acta Endocrinol. 101: 562–569.
Acknowledgements
We are grateful to the Medical Research Council for grant support, to Brahms Diagnostics and to Dr Gilbert Vassart (Brussels) for supply of reagents, to Michelle Haughton for technical support and to Theresa King for manuscript preparation.
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Ludgate, M., Gire, V., Crisp, M. et al. Contrasting effects of activating mutations of GαS and the thyrotropin receptor on proliferation and differentiation of thyroid follicular cells. Oncogene 18, 4798–4807 (1999). https://doi.org/10.1038/sj.onc.1202864
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DOI: https://doi.org/10.1038/sj.onc.1202864
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