Geoffrey N. Hendy
Professor of Medicine, McGill University
Associate Director, Calcium Research Laboratory
Associate Member, Hormones and Cancer Research Unit
Associate Member, Departments of Physiology and Human Genetics
The work of my laboratory is focused on understanding parathyroid function in health and disease at the molecular level. The calcium-sensing receptor (CASR) on the plasma membrane of parathyroid endocrine cells acts as a ‘calciostat’ to sense the blood calcium level and regulate parathyroid hormone (PTH) secretion and parathyroid cell growth. The expression level and/or activity of the CASR is of paramount importance. In regard to altered CASR expression, we have demonstrated that both vitamin D and cytokines are positive regulators and we have characterized response elements to these factors in the CASR gene regulatory regions. With respect to altered activity, our molecular genetic analysis in hypercalcemic and hypocalcemic patients has identified inactivating and activating CASR mutations, respectively. Functional analysis of the mutants provides insight into the workings of the receptor. The CASR is important in mediating the effects of extracellular calcium in maintaining a differentiated state and inhibiting cell growth. For example, loss of CASR expression in colon crypt epithelia may be associated with abnormal differentiation and/or malignant progress. Menin, a tumor suppressor responsible (when inactivated) for the inherited disorder multiple endrocrine neoplasia type 1, is also often mutated in the common disorder, sporadic primary hyperparathyroidism. Transforming growth factor-ß (TGF-ß) is an important growth inhibitory cytokine. We have shown that menin inactivation leads to loss of TGF-ß inhibition of parathyroid cell proliferation and PTH secretion. Chromogranin A, a dense-core secretory granule protein, that is expressed in neuroendocrine cells along with other members of the granin family of acidic glycoprotein, is widely used for the pathological diagnosis of neuroendocrine neoplasms. We have generated a mouse mutant null for the Chga gene. In this model, there is increased expression of the other granins likely compensating for the CgA deficiency and maintaining these mice in a relatively unimpaired state.
- Lucie Canaff
- Karin Schorr
- Svetlana Pidasheva
- Xiang Zhou
- Yaroslava Chtompel
Canaff, L. and Hendy, G.N. Calcium-sensing receptor gene transcription is upregulated by the proinflammatory cytokine, interleukin-1beta: Role of the NF-kappa B pathway and kappa B elements. J Biol Chem, 280:14177-141188. 2005.
Pidasheva, S., Canaff, L., Simonds, W.F., Marx, S.J., Hendy, G.N. Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia. Human Mol Genet. 14:1679-1690, 2005.
Chakarabarty, S., Wang, H., Canaff, L., Hendy, G.N., Appelman, H., Varani, J. Calcium sensing receptor in human colon carcinoma: interaction with Ca2+ and 1,25-dihydroxyvitamin D3. Cancer Res. 65:493-498, 2005.
Hendy, G.N., Kaji, H., Sowa, H., Lebrun, J-J., Canaff, L. Menin and TGF-ß superfamily member signaling via the Smad pathway in pituitary, parathyroid and osteoblast. Invited Review. Multiple Endocrine Neoplasia 2004 Workshop edition. Eds. S.J. Marx and C.A. Stratakis. Horm. Metab. Research, 37:375-379, 2005.
Hendy, G.N., Li, T., Girard, M., Feldstein, R.C., Mulay, S., Desjardins, R., Day R., Karaplis, A.C., Tremblay, M.L., Canaff, L. Targeted ablation of the chromograning A (Chga) gene: normal neuroendocrine dense core secetory granules and increased expression of other granins. Molec, Endocrinol, In Press. Epub 2006.