In most cells, the second messenger cAMP inhibits cellular proliferation by interfering with signaling through the mitogen activated protein kinase pathway. But in a subset of endocrine cells, notably in somatotrophs of the anterior pituitary and in thyroid follicular cells, cAMP is actually a mitogen which mediates hormonal signals arising from the hypothalamus and pituitary, respectively. The goal of our proposal is to test the hypothesis that cAMP induces endocrine cell proliferation via the cAMP responsive factor CREB. We will test whether, in response to cAMP induction, phosphorylation of CREB at the PK-A phospho acceptor site Ser 133 promotes cellular proliferation by inducing the expression of specific target genes which function as endocrine-specific cell-cycle regulators. These studies may have important implications in the treatment of a number of endocrine diseases such as acromegaly (somatotroph tumors) and Grave's disease (thyroid), where inappropriate activation of the cAMP pathway leads to neoplastic transformation.
