Mechanisms involved in coupling receptor activation to cyclic AMP (CAMP) production have been studied intensively. An understanding of how CAMP regulates gene expression is beginning to unfold with the discovery of the CREB family of transcription factors, and CAMP inducible transcription factors such as jun, fos, and the tissue-specific factors GHF1/pit1 and TTF1. Much less is known, however, about how CAMP regulates normal mitogenesis. The link between abnormal regulation of other modes of signal transduction, such as phosphatidylinositol turnover or tyrosine kinase action, and tumorigenesis has been undisputed for years given the large number of oncogenes which directly activate these pathways. In contrast putative oncogenes which function along the CAMP pathway, gasp and gip2, were only reported within the last year. Nevertheless, CAMP is essential for growth and differentiation in a wide variety of cells, particularly in the endocrine system. The thyroid follicular cell, for example, is dependent on thyroid stimulating hormone and the resultant increase in intracellular CAMP not only for thyroid hormone synthesis but for cell division as well. The goal of this proposal is to further our understanding of how key regulatory molecules along the CAMP pathway control the normal process of thyroid cell division, and how aberrant regulation of the CAMP signal may lead to thyroid adenoma or carcinoma. Preliminary results from this laboratory provide direct evidence implicating CAMP-induced gene expression and CREB in the induction of cell division by CAMP in the thyroid. The first major goal of this proposal will be to determine the mechanism by which the CREB family of transcription factors normally regulates cell division in the thyroid follicular cell. We will use cell microinjection to examine which CREB gene products, and which genes induced by CREB, such as c-jun, c-fos, and possibly TTF1 are required for the effect. The second major goal will be to attempt to develop a method for the identification of novel genes which deregulate the CAMP pathway, using DNA transfer into the FRTL5 cell line. Understanding the mechanisms underlying CAMP-mediated thyroid cell growth is important not only because of the relevance of this pathway in thyroid adenoma formation, but also because similar mechanisms may be involved in the pathogenesis of hyperplastic and neoplastic states in endocrine as well as other cell types.

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