BBB seminar: Jacques E. Dumont
Thyroid tumorigenesis: from mitogenic pathways to human tumors
Jacques E. Dumont, Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire (IRIBHM), Universite Libre de Bruxelles, Faculte de Medecine, Brussels, Belgium
The growth and proliferation of the normal human thyroid cell is controlled by several regulating cascades: the cAMP cascade, including the assembly and nuclear translocation of the complex of cyclin D3-CDK4, the EGF signaling cascade, and signaling via the IGF-1 receptor and PI3 kinase.
Mice expressing the adenosine A2 receptor, which behaves as a constitutive activator of adenylate cyclase in the thyroid, develop a hyperfunctioning adenoma involving the whole gland: they are hyperthyroid and have a goiter. Mice expressing the Ret PTC oncogene, which activates, somewhat as EGF, a growth factor cascade, develop a goiter and later what appears as papillary carcinomas. Mice overexpressing both human IGF-1 and IGF-1 receptor have an enlarged thyroid and some degree of autonomy (as shown by a decreased TSH serum level) but no tumor.
Human diseases illustrate the concepts. Defective TSH receptors cause hypothyroidism. Congenital constitutive activation of the TSH receptor leads to congenital hyperthyroidism. Constitutive activation of Gsa, the G protein intermediate between the TSH receptor and adenylate cyclase, causes the McCune Albright syndrome, which entails goiter and hyperthyroidism. Mutations activating the TSH receptor of Gsa in the thyroid cells give rise to 80% of autonomous adenomas
Papillary carcinomas, in which the abnormal expression of Ret (in a constitutive form resulting from a gene translocation linking the active part of the receptor to a dimerizable domain of another protein) allows the take over of the growth factor pathways, exhibit uncontrolled growth and dedifferentiation.
The pitfalls in relying on cell lines to predict in vivo biology will be discussed.
Jacques E. Dumont
Prof. Dumont is a pioneer in cell signaling research in Europe, and the world leader in the study of thyroid biology. He has established an interdisciplinary research institute (IRIBHM) affiliated with the medical faculty of the Free University of Brussels. Among his recent achievements are the identification of mutations of the TSH receptor leading to thyroid disease, and the establishment of the goitrogenicity of cAMP by overstimulation of this pathway in transgenic mice.