The focus of the present application is to better define some of the molecular events which underlie the initiation and progression of thyroid malignancies. The investigator postulates that the potential for thyroid cell transformation is determined in part by the nature of the genetic events responsible for the initiation of the tumor clone, and specifically is dependent on whether these events promote genetic instability. In this proposal, they will examine the role of individual thyroid tumor initiating events on indicators of chromosomal stability in vitro. The major emphasis will be to determine the effect of inducible expression of several oncogene products on the generation of anomalous chromosome structures and mitosis, on the rate of gene amplification, and on generation of DNA strand breaks. In addition, the investigators will examine the phenotypic impact of inducing thyroid-specific expression of wild-type and mutant PKC alpha isoforms in transgenic mice. Finally, the role of mutations of PKC alpha in the control of thyroid-differentiated gene expression will be studied.
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