THYROTROPIN VIA CYCLIC-AMP INDUCES INSULIN-RECEPTOR EXPRESSION AND INSULIN CO-STIMULATION OF GROWTH AND AMPLIFIES INSULIN AND INSULIN-LIKE GROWTH-FACTOR SIGNALING PATHWAYS IN DOG THYROID EPITHELIAL-CELLS

Despite the similarity of their receptors and signal transduction path ways, insulin is regarded as a regulator of glucose, protein, and lipi d metabolism, whereas insulin-like growth factors (IGF-I and IGF-II) m ainly act as mitogenic hormones. In the dog thyroid primary culture mo del, the triggering of DNA synthesis by thyrotropin (TSH) through cAMP , or by cAMP-independent factors including epidermal growth factor, he patocyte growth factor and phorbol esters, requires insulin or IGFs as comitogenic factors. In the present study, in TSH-treated cells, IGF- I receptors and insulin receptors were paradoxically equivalent in the ir capacity to elicit the comitogenic pathway, which, however, was med iated only by IGF-I receptors in dog thyroid cells stimulated by cAMP- independent mitogens. Moreover, prior cell exposure to TSH or forskoli n increased their responsiveness to insulin, IGF-I, and IGF-II, as see n on DNA synthesis and activation of a common insulin/IGF signaling pa thway. To understand these observations, binding characteristics and e xpression of insulin and IGF-I receptors were examined. To analyze IGF -I receptor characteristics, the unexpected interference of a huge pre sence of IGF-binding proteins at the cell membrane was avoided using l abeled Long R(3) IGF-I instead of IGF-I, Strikingly, TSH, through cAMP , time-dependently induced insulin binding and insulin receptor mRNA a nd protein accumulation without any effect on IGF-I receptors. These f indings constitute a first example of an induction of insulin receptor gene expression by a cAMP-mediated hormone, In dog thyroid cells, thi s allows low physiological insulin concentrations to act as a comitoge nic factor and might explain in part the enhanced responsiveness to IG Fs in response to TSH. This raises the possibility that TSH-insulin in teractions may play a role in the regulation of thyroid growth and fun ction in vivo.