This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Heinrich, R. Articles by Kraiem, Z. Search for Related Content PubMed PubMed Citation Articles by Heinrich, R. Articles by Kraiem, Z.

The Protein Kinase A Pathway Inhibits c-jun and c-fos Protooncogene Expression Induced by the Protein Kinase C and Tyrosine Kinase Pathways in Cultured Human Thyroid Follicles¹

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.

This article has been cited by other articles:

				S. Romano, A. Muscella, C. Storelli, and S. Marsigliante Angiotensin II does not stimulate proliferation of rat thyroid PC Cl3 cell line J. Endocrinol., December 1, 2006; 191(3): 727 - 735. [Abstract] [Full Text] [PDF]

				S. Paternot, J. E. Dumont, and P. P. Roger Differential Utilization of Cyclin D1 and Cyclin D3 in the Distinct Mitogenic Stimulations by Growth Factors and TSH of Human Thyrocytes in Primary Culture Mol. Endocrinol., December 1, 2006; 20(12): 3279 - 3292. [Abstract] [Full Text] [PDF]

				A. Shih, S. Zhang, H. J. Cao, H.-Y. Tang, F. B. Davis, P. J. Davis, and H.-Y. Lin Disparate Effects of Thyroid Hormone on Actions of Epidermal Growth Factor and Transforming Growth Factor-{alpha} Are Mediated by 3',5'-Cyclic Adenosine 5'-Monophosphate-Dependent Protein Kinase II Endocrinology, April 1, 2004; 145(4): 1708 - 1717. [Abstract] [Full Text] [PDF]

				T. C. Peterson, M. R. Peterson, H. A. Robertson, M. During, and M. Dragunow Selective Down-Regulation of c-jun Gene Expression by Pentoxifylline and c-jun Antisense Interrupts Platelet-Derived Growth Factor Signaling: Pentoxifylline Inhibits Phosphorylation of c-Jun on Serine 73 Mol. Pharmacol., June 1, 2002; 61(6): 1476 - 1488. [Abstract] [Full Text] [PDF]

				T. Kimura, A. Van Keymeulen, J. Golstein, A. Fusco, J. E. Dumont, and P. P. Roger Regulation of Thyroid Cell Proliferation by TSH and Other Factors: A Critical Evaluation of in Vitro Models Endocr. Rev., October 1, 2001; 22(5): 631 - 656. [Abstract] [Full Text] [PDF]

				N. Fernandez, M. J. Caloca, G. V. Prendergast, J. L. Meinkoth, and M. G. Kazanietz Atypical Protein Kinase C-{zeta} Stimulates Thyrotropin-Independent Proliferation in Rat Thyroid Cells Endocrinology, January 1, 2000; 141(1): 146 - 152. [Abstract] [Full Text] [PDF]

				S. Korem, M. B. Resnick, and Z. Kraiem Similar and Divergent Patterns in the Regulation of Matrix Metalloproteinase-1 (MMP-1) and Tissue Inhibitor of MMP-1 Gene Expression in Benign and Malignant Human Thyroid Cells J. Clin. Endocrinol. Metab., September 1, 1999; 84(9): 3322 - 3327. [Abstract] [Full Text]

				T. Hara, H. Namba, N. Takamura, T.-T. Yang, Y. Nagayama, S. Fukata, K. Kuma, N. Ishikawa, K. Ito, and S. Yamashita Thyrotropin Regulates c-Jun N-Terminal Kinase (JNK) Activity through Two Distinct Signal Pathways in Human Thyroid Cells Endocrinology, April 1, 1999; 140(4): 1724 - 1730. [Abstract] [Full Text]

				M. Derwahl, M. Broecker, and Z. Kraiem Thyrotropin May Not Be the Dominant Growth Factor in Benign and Malignant Thyroid Tumors J. Clin. Endocrinol. Metab., March 1, 1999; 84(3): 829 - 834. [Full Text]