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
R. Burikhanov et al., 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, The Journal of biological chemistry, 271(46), 1996, pp. 29400-29406
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.