In the first area of focus, molecular mechanisms causative for hereditary and sporadic medullary thyroid cancer, the laboratory has worked extensively with in vitro cell culture models of medullary thyroid carcinoma, three of which were established and characterized by members of the laboratory. Using these models, members of the laboratory have elucidated the role of the RET proto-oncogene in the development of medullary thyroid carcinoma.
They have also characterized the role of the calcium-sensing receptor in human disease and defined mechanisms for alternative RNA processing of the calcitonin gene.
More recently, they demonstrated that RET, upon activation, is translocated to the nucleus where it interacts with the transcription factor ATF4 which, in turn, leads to its down regulation and an inhibition of apoptosis.
It is now clear that this is the major mechanism by which RET activation leads to cellular transformation. Future goals for the laboratory include the identification of other nuclear factors with which RET interacts and whether this information can be used therapeutically to treat medullary thyroid carcinoma.
The second major area of focus is the mechanism by which the hormone, calcitonin, regulates bone resorption and formation. In collaboration with Allan Bradley, the laboratory created a global knockout of the calcitonin gene.
Interestingly, this model demonstrated increased bone formation. Long-term follow-up of the model (two-to-three years), however, demonstrated a predominant osteoclastic phenotype with profound increase in bone resorption and bone remodeling. A long-term goal of the laboratory is to better understand how this hormone regulates bone remodeling.