The 3',5'-cyclic adenosine monophosphate response element binding protein (CREB) is functionally reduced in human toxic thyroid adenomas

In human normal thyrocytes, the cAMP-responsive signaling pathway plays a c entral role in gene regulation, cell proliferation, and differentiation. Co nstitutive activation of the cAMP signal transduction system has been docum ented in thyroid autonomously hyperfunctioning adenomas in which activating mutations in either the TSH receptor gene or the Gs alpha protein gene (gs p oncogene) have been described. The molecular mechanism whereby cAMP induc es thyrocyte proliferation is unknown, but recent evidence suggests that th e transcription factor cAMP response element binding protein (CREB) may ser ve as an important biochemical intermediate in this proliferative response. Herein we have investigated the expression of CREB in normal and tumoral t hyroid tissues from a series of ten unrelated patients with autonomously hy perfunctioning adenomas, previously screened for mutations in the TSH recep tor and Gs alpha genes. rn an tumors examined, the expression of the activa ted, phosphorylated form of CREB was markedly reduced compared with that of the corresponding paired normal thyroid tissue, and this reduction was ind ependent of the presence of mutations in the TSH receptor gene and Gs alpha gene. Moreover, no correlation was observed in these tissues between CREB phosphorylation and either protein kinase A activity or protein phosphatase expression. Thus, these data suggest that in human hyperfunctioning thyroi d adenomas, the PKA/CREB system does not play a role in cell proliferation.