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Volume 271, Number 46,
Issue of November 15, 1996
pp. 29400-29406
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
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
(Received for publication, June 6, 1996, and in revised form, July 29, 1996)
Ravshan
Burikhanov
,
Katia
Coulonval
,
Isabelle
Pirson
,
Françoise
Lamy
,
Jacques E.
Dumont
and
Pierre P.
Roger
From the Institute of Interdisciplinary Research, Université
Libre de Bruxelles, Campus Erasme, 1070 Brussels, Belgium
Despite the similarity of their receptors and
signal transduction pathways, insulin is regarded as a regulator of
glucose, protein, and lipid metabolism, whereas insulin-like growth
factors (IGF-I and IGF-II) mainly act as mitogenic hormones. In the dog thyroid primary culture model, the triggering of DNA synthesis by
thyrotropin (TSH) through cAMP, or by cAMP-independent factors including epidermal growth factor, hepatocyte 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 their capacity to elicit the comitogenic
pathway, which, however, was mediated only by IGF-I receptors in dog
thyroid cells stimulated by cAMP-independent mitogens. Moreover, prior
cell exposure to TSH or forskolin increased their responsiveness to
insulin, IGF-I, and IGF-II, as seen on DNA synthesis and activation of
a common insulin/IGF signaling pathway. To understand these
observations, binding characteristics and expression of insulin and
IGF-I receptors were examined. To analyze IGF-I receptor
characteristics, the unexpected interference of a huge presence of
IGF-binding proteins at the cell membrane was avoided using labeled
Long R3 IGF-I instead of IGF-I. Strikingly, TSH, through
cAMP, time-dependently induced insulin binding and insulin
receptor mRNA and protein accumulation without any effect on IGF-I
receptors. These findings constitute a first example of an induction of
insulin receptor gene expression by a cAMP-mediated hormone. In dog
thyroid cells, this allows low physiological insulin concentrations to
act as a comitogenic factor and might explain in part the enhanced
responsiveness to IGFs in response to TSH. This raises the possibility
that TSH-insulin interactions may play a role in the regulation of
thyroid growth and function in vivo.

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Copyright © 1996 by the American Society for Biochemistry and Molecular Biology.
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