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Experimental Studies |
Endocrine Research Unit, Carmel Medical Center and the Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Address all correspondence and requests for reprints to: Z. Kraiem, Ph.D., Endocrine Research Unit, Carmel Medical Center, 7 Michal Street, Haifa 34362, Israel.
We have previously demonstrated antagonistic interactions between the
major signal transduction pathways in human thyroid follicles: TSH
acting via protein kinase A (PKA) attenuated phorbol ester [acting via
protein kinase C (PKC)] as well as epidermal growth factor
(EGF)-protein tyrosine kinase (PTK)-mediated cell proliferation,
whereas the PKC and PTK pathways inhibited PKA-mediated cell
differentiation. In view of the key role played by the protooncogenes
c-jun and c-fos in the cascade of events leading
to cell proliferation and differentiation, we examined whether the
antagonism we observed between the pathways could be related to changes
in the expression of these genes. The experimental model used was the
same in vitro system as that used in the above study on
cell growth and differentiation: thyroid follicles of human origin
cultured in suspension under serum-free conditions. Both EGF (1–50
ng/mL) and the phorbol ester 12-O-tetradecanoylphorbol
13-acetate (TPA; 10-11-10-7 mol/L) dose and
time dependently stimulated c-jun and c-fos
messenger ribonucleic acid (mRNA) expression. The c-jun and
c-fos mRNA stimulation elicited by TPA was reduced by the
PKC inhibitors, chelerythrine and staurosporine, and could not be
mimicked by 4
-phorbol 12,13-didecanoate (a phorbol ester that fails
to activate PKC), whereas the stimulation induced by EGF was diminished
by the PTK inhibitor, genistein. This indicates a PKC- and PTK-mediated
pathway triggered by TPA and EGF, respectively. TSH induced an increase
in c-jun and c-fos mRNA, which, though
significant, was small compared to that elicited by TPA or EGF.
Addition of TSH (0.1–0.5 mU/mL), however, to either TPA or EGF dose
dependently inhibited the c-jun and c-fos mRNA
elicited by these agents. The repressive action of TSH on the effects
of TPA and EGF mRNA were mimicked by forskolin and 8-bromo-cAMP,
suggesting that the TSH inhibitory action is PKA mediated. The TSH
inhibitory action seems to require de novo protein
synthesis, as it was abrogated in the presence of cycloheximide.
In conclusion, the present study provides novel data on c-jun and c-fos gene expression and their modulation by the major signal transduction pathways operating in human thyrocytes. Moreover, using the same serum-free system of human thyroid follicles cultured with the same agents and at the same doses as in our previous study on cell growth and differentiation, we found the TSH/PKA pathway to inhibit PKC- and EGF/tyrosine kinase-induced c-jun and c-fos mRNA, i.e. antagonistic effects parallel to those previously observed measuring cell proliferation. The findings suggest an association between human thyroid cell proliferation and c-jun and c-fos gene expression.
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