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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1839-1844
Copyright © 1997 by The Endocrine Society

Experimental Studies

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

R. Heinrich and Z. Kraiem

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.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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{alpha}-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.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
OUR BROAD objective has been to delineate the role of the major signal transduction pathways believed to be implicated in the control of human thyroid cell growth and differentiation: the protein kinase A (PKA), protein kinase C (PKC), and protein tyrosine kinase (PTK)-mediated mechanisms. The experimental model used for this purpose has been our system of thyroid follicles of human origin cultured in suspension under serum-free conditions in which the follicular three-dimensional structure is retained (1). We have previously demonstrated a considerable degree of cross-talk between the signal transduction pathways in such human thyroid follicles (2). In particular, our results point to antagonistic interactions between the signal transduction pathways; PKC and epidermal growth factor (EGF), acting via tyrosine kinase, inhibited TSH (PKA)-mediated cell differentiation, as expressed by iodide uptake, organification, and thyroid hormone secretion (2). Conversely, TSH attenuated PKC- as well as EGF-mediated cell proliferation (2). Our present aim has been to explore the possible underlying mechanism(s) causing these antagonistic interactions.

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 (reviewed in Refs. 3 and 4), we examined whether the antagonism we observed between the pathways could be related to changes in the expression of these genes. For this purpose we used the same serum-free in vitro system of human thyroid follicles and the same agents as probes of the signal transduction pathways: TSH, forskolin, and 8-bromo cAMP (8-Br-cAMP) acting via PKA, EGF as activator and genistein as inhibitor of tyrosine kinase, and phorbol ester as activator and staurosporine and chelerythrine as inhibitors of the PKC-mediated pathway.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Cell culture

The method of preparation of human thyroid follicles from colloid goiter tissue obtained at thyroidectomy from nodular goiter patients has been previously described in detail (1, 2). TSH (500 µU/mL) was added to the collagen suspension in a serum-free medium [DCCM-1, which contains insulin (1 µg/mL) with no other hormone or growth factor] for 4 days to induce follicle formation. The medium was then removed, and fresh serum-free medium was added in the absence of TSH and cultured for an additional 3 days, at the end of which the test agent (e.g. TSH, TPA, or EGF) was added; the control consisted of serum-free medium alone. Culture for 3 days in the absence of TSH in serum-free medium was necessary before the addition of test agent so as to free the cells from any prior TSH influence.

We verified that the cell culture design described above 1) allowed follicle structure to be retained despite absence of TSH for the last 3 days of culture, and 2) avoided cell desensitization to TSH as a result of exposure to the hormone for the first 4 days of culture. Indeed, electron microscopy demonstrated cells in follicle arrangement with normal polarity, and the cells were shown to be responsive, as shown by a 25-fold rise in cAMP formation after exposure to TSH.

Ribonucleic acid (RNA) isolation and analysis

The following method was established for determination by Northern blot of messenger RNA (mRNA) c-jun and c-fos levels in cultured human thyroid cells after an investigation for optimal conditions. Total RNA was extracted from thyroid cells with Tri-reagent. The RNA samples were denatured by heating at 65 C for 15 min in 2 mol/L formaldehyde-50% formamide and fractionated by electrophoresis (7 µg/lane) in 1% agarose gel containing 0.66 mol/L formaldehyde and MOPS buffer. After separation, the RNA was transferred to a nylon membrane (Hybond-N). c-jun and c-fos mRNA were detected by hybridization with oligonucleotide probes 5'-end labeled with 32P, autoradiographed at -70 C, and quantitated by densitometry. The densitometric values were normalized to those for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Probing, stripping, and reprobing of c-jun, c-fos, and GAPDH were performed on the same membrane.

The Northern blot method used for mRNA estimation does not allow any distinction to be made between transcriptional activation and stabilization of the mRNA. The use of cycloheximide as a protein synthesis inhibitor should be cautioned with the remark that this agent, like other inhibitors of protein synthesis, has been shown not only to be able to block translation but also to be capable of inducing immediate early gene expression (5).

Each experiment was repeated at least three times, using cell preparations obtained from separate patients. The mRNA data shown in the figures and in the text are GAPDH normalized. Statistical analysis of the data was performed using Student’s t test when two treatments were compared and ANOVA when more than two treatments were evaluated (e.g. dose-dependent responses). P < 0.05 was considered significant.

Materials

Materials needed for cell culture and all agents used were obtained as described previously (2). For RNA isolation and analysis, the following sources were used: Tri-reagent from Molecular Research Center (Cincinnati, OH); Hybond-N from Amersham International (Amersham, Bucks, UK); c-jun, c-fos, and GAPDH oligonucleotide probes from Oncogene Science (Cambridge, MA); all other materials from Sigma Chemical Co. (St. Louis, MO).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Effects of stimulating the PKC, PTK, and PKA pathways on c-jun and c-fos mRNA levels

The time courses of phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA)- and EGF-induced c-jun and c-fos mRNA demonstrate a rapid and transient increase in levels of the protooncogenes (Fig. 1Go, A and B). It should be kept in mind that exposure of cells to TPA for longer than 3 h may induce PKC down-regulation (6). Dose-response experiments showed that the concentrations used for the above kinetic studies, i.e. 10-7 mol/L TPA and 25 ng/mL EGF, were maximal (TPA at 10-11, 10-9, and 10-7 mol/L: 223 ± 15%, 584 ± 48%, and 1884 ± 145% (mean ± SE) of the control mRNA for c-jun and 165 ± 14%, 196 ± 18%, and 1640 ± 132% of the control mRNA for c-fos; EGF at 1, 5, 25, and 50 ng/mL: 405 ± 38%, 496 ± 40%, 651 ± 54%, and 646 ± 52% of the control mRNA for c-jun mRNA).



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  		Figure 1. Time course of c-jun and c-fos mRNA levels in cultured human thyroid follicles exposed to TPA (A) or EGF (B). After culture for 7 days, TPA (10-7 mol/L) or EGF (25 ng/mL) was added to the culture medium for various periods, and c-jun and c-fos mRNA were measured by Northern blot followed by densitometry. Each point represents the mean ± SE of three experiments.

 
The c-jun and c-fos mRNA stimulation elicited by TPA was reduced by the PKC inhibitors, chelerythrine and staurosporine, and could not be reproduced by the inactive phorbol ester, 4{alpha}-phorbol 12,13-didecanoate (Fig. 2AGo). The stimulation induced by EGF was diminished by the tyrosine kinase inhibitor, genistein (Fig. 2BGo).



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  		Figure 2. Effects of chelerythrine or staurosporine on TPA-induced (A) or of genistein on EGF-induced (B) jun and c-fos mRNA in cultured human thyroid follicles. After culture for 7 days, chelerythrine (chel.; 0.1 µmol/L), staurosporine (SS; 1 or 20 nmol/L), or genistein (50 or 100 µmol/L) was added, followed 30 min later by 10-7 mol/L TPA (in the dishes containing chelerythrine or staurosporine) or 25 ng/mL EGF (in the dishes containing genistein), and culture was continued for an additional hour. TPA (10-7 mol/L), EGF (25 ng/mL), and 4{alpha}-phorbol 12,13-didecanoate (4{alpha}; 10-7 mol/L) were also cultured alone for 1 h. c-jun and c-fos mRNA were then measured by Northern blot, followed by densitometry. Each bar represents the mean ± SE of three experiments. *, P < 0.05; **, P < 0.01; ***, P < 0.001 [compared to TPA alone (A) and compared to EGF alone (B)].

 
c-jun and c-fos mRNA levels rose to 253 ± 15% and 190 ± 13% of the control value, respectively, after exposure of cells to TSH (Fig. 3Go). This stimulation, although significant compared to the control value, was small compared to that elicited by TPA or EGF (compare, for example, the effects of TSH and TPA in Fig. 3Go). Exposure of cells to TSH at different concentrations (10–1000 µU/mL) and for different time periods (2 min to 24 h) did not augment c-jun and c-fos mRNA levels any further than noted above (i.e. Fig. 3Go). The cAMP-elevating agents, forskolin (20 µmol/L) and 8-Br-cAMP (1 mmol/L), like TSH, evoked a relatively small stimulation of c-jun and c-fos mRNA (170 ± 12% and 152 ± 10% control for c-jun and c-fos mRNA, respectively, regarding forskolin and 134 ± 8% and 161 ± 11% control for c-jun and c-fos mRNA, respectively, regarding 8-Br-cAMP; P < 0.05 compared to control; after 90 min exposure to the agents; data not shown).



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  		Figure 3. Effects of TSH, TPA, and TSH plus TPA in the absence and presence of cycloheximide on c-jun and c-fos mRNA in cultured human thyroid follicles. After culture for 7 days, TSH (0.5 mU/mL), TPA (10-7 mol/L), or TSH (0.5 mU/mL) plus TPA (10-7 mol/L) were added in the absence and presence of cycloheximide (10 µg/mL; added 20 min before the addition of TSH, TPA, or TSH plus TPA), and culture was continued for an additional hour. c-jun and c-fos mRNA were then measured by Northern blot followed by densitometry. Each bar represents the mean ± SE of three experiments. *, P < 0.05; **, P < 0.001 [compared to control (without cycloheximide)].

 
Effects of stimulating the PKA pathway on TPA- and EGF-induced mRNA levels

Figure 3Go shows that addition of TSH to TPA elicited a marked drop in mRNA protooncogene levels (P < 0.01 compared to TPA alone for c-jun and c-fos. TSH inhibited such protooncogene expression in a dose-dependent fashion (P < 0.05; Fig. 4AGo). As with the phorbol ester, TSH also dose-dependently inhibited (P < 0.01) EGF-induced c-jun and c-fos mRNA (Fig. 4BGo). The repressive action of TSH on the TPA- and EGF-induced mRNA effects were mimicked by forskolin and 8-Br-cAMP (TPA/EGF alone compared to TPA/EGF plus forskolin/8-Br-cAMP: P < 0.01 for c-jun and P < 0.05 for c-fos; Fig. 5Go).



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  		Figure 4. Effects of TSH on TPA (A)- or EGF (B)-induced c-jun and c-fos mRNA in cultured human thyroid follicles. After culture for 7 days, TPA (10-7 mol/L) or EGF (25 ng/mL) were added in the absence and presence of TSH (added at various concentrations 30 min before the addition of TPA or EGF), and culture was continued for an additional hour. c-jun and c-fos mRNA were then measured by Northern blot followed by densitometry. Each bar represents the mean ± SE of three experiments. The autoradiographs shown are those of a representative experiment.

 


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  		Figure 5. Effects of TSH, 8-Br-cAMP, or forskolin on TPA- or EGF-induced c-jun and c-fos mRNA in cultured human thyroid follicles. After culture for 7 days, TPA (10-7 mol/L) or EGF (25 ng/mL) was added in the absence and presence of TSH (0.5 mU/mL), 8-Br-cAMP (1 mmol/L), or forskolin (20 µmol/L; added 30 min before the addition of TPA or EGF). Culture was continued for an additional hour, and c-jun and c-fos were then measured by Northern blot, followed by densitometry. Each bar represents the mean ± SE of three experiments. The autoradiograph shown is that of a representative experiment

 
c-jun and c-fos mRNA expression in the presence of the protein synthesis inhibitor, cycloheximide

Figure 3Go shows that addition of cycloheximide increased c-jun and c-fos mRNA levels in control cells as well as in cells exposed to TSH (P < 0.005 compared to TSH alone) or TPA (P < 0.05 compared to TPA alone). Addition of cycloheximide also stimulated such mRNA levels in cells exposed to EGF (600 ± 42% and 700 ± 53% of the control value in the absence to 1050 ± 84% and 1235 ± 96% of the control value in the presence of cycloheximide, for c-jun and c-fos, respectively; P < 0.05; data not shown). The presence of cycloheximide abolished the TSH inhibitory action on TPA-induced c-jun and c-fos mRNA (Fig. 3Go). Moreover, TSH, 8-Br-cAMP, and forskolin failed to inhibit EGF-induced mRNA when cycloheximide was present (Fig. 6Go).



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  		Figure 6. Effects of TSH, 8-Br-cAMP, or forskolin in the presence of cycloheximide on EGF-induced c-jun and c-fos mRNA in cultured human thyroid follicles. After culture for 7 days, cycloheximide (10 µg/mL) was added in the absence and presence of TSH (0.5 mU/mL), 8-Br-cAMP (1 mmol/L), or forskolin (20 µmol/L), followed 30 min later by the addition of EGF (25 ng/mL). Culture was continued for an additional hour, and c-jun and c-fos were measured by Northern blot, followed by densitometry. Each bar represents the mean ± SE of three experiments. *, P < 0.01; **, P < 0.001 (compared to control).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Few studies have been reported on c-jun expression in thyroid cells. The phorbol ester TPA in FRTL-5 cells (7), TPA and EGF in canine thyrocytes (8), and insulin-like growth factor I (IGF-I), which, like EGF, is believed to act via tyrosine kinase, in Wistar rat thyroid (WRT) cells (9), enhanced c-jun mRNA. TSH, on the other hand, inhibited basal c-jun mRNA in canine (8) and WRT (9) thyrocytes, whereas in FRTL-5 cells the hormone stimulated the expression of the protooncogene (7, 10). Regarding c-fos expression, EGF in porcine thyroid cells (11); TPA (12), EGF (12), and carbachol (acting via Ca2+/phosphatidylinositol) (13) in canine thyroid cells; IGF-I in WRT cells (9); and IGF-I, insulin (acting via tyrosine kinase), TPA, and basic fibroblast growth factor in FRTL-5 cells (14, 15), induced c-fos mRNA. TSH stimulated c-fos mRNA expression in canine (12), WRT (9), and FRTL-5 cells (10, 14, 15, 16, 17) and enhanced c-fos promoter activity in FRTL-5 cells (18). In porcine thyrocytes, however, TSH was devoid of any effect on c-fos mRNA expression (11).

The present study provides the first report on c-jun mRNA expression and its modulation in thyroid cells of human origin and the second regarding c-fos mRNA; a previous study showed that TSH and insulin induced c-fos mRNA in human fetal thyroid monolayer cells (19). It should be pointed out that the human thyroid follicles used in the present study were derived from goitrous tissue, which may have affected growth regulation of these cells. We have demonstrated that TPA and EGF stimulate c-jun and c-fos mRNA expression in a time- and dose-dependent manner; the dose-response relationship was never previously reported for the effect of these agents on c-jun expression in thyroid cells. Moreover, the c-jun and c-fos mRNA stimulation elicited by TPA could not be mimicked by 4{alpha}-phorbol 12,13-didecanoate, a phorbol ester that fails to activate PKC, and were reduced by the PKC inhibitors, chelerythrine and staurosporine. The c-jun and c-fos mRNA stimulation induced by EGF, on the other hand, was diminished by genistein, a tyrosine kinase inhibitor. The TPA and EGF actions seem, therefore, to be mediated by PKC and PTK pathways, respectively. PKC involvement in the TPA action was never previously shown in thyroid cells regarding c-jun expression and, with respect to c-fos, was found only in FRTL-5 cells (14). As expected of immediate early genes, c-jun and c-fos mRNA levels rose in a rapid transient fashion and were superinduced in the presence of an inhibitor of protein synthesis. This superinduction was observed not only with regard to TPA- and EGF-induced mRNA, but also with TSH which, in the absence of cycloheximide, could only stimulate c-jun and c-fos mRNA weakly compared to that elicited by the phorbol ester and growth factor.

Regarding interactions between the PKA and PKC/PTK pathways, TSH managed to dose-dependently inhibit TPA- as well as EGF-induced c-jun and c-fos mRNA. The repressive action of TSH on the TPA and EGF mRNA effects were mimicked by forskolin and 8-Br-cAMP, suggesting that the TSH inhibitory action is PKA mediated. Moreover, the TSH inhibitory action seems to require de novo protein synthesis, as it was abrogated in the presence of cycloheximide. The data suggest, therefore, PKA mediation via newly synthesized, rather than preexisting, proteins in the cultured cells.

We demonstrated an inhibitory influence by TSH/PKA on TPA/PKC-induced c-jun and c-fos mRNA in thyroid cells. This is consistent with observations in mouse fibroblasts (20, 21) and mouse T lymphocytes (22) regarding c-jun, but not c-fos, mRNA in these cells in which PKA together with TPA additively (21) or synergistically (22) stimulated expression of the c-fos protooncogene. There are no other reports on interactions of the PKA and PKC pathways on c-fos mRNA expression in thyroid cells, whereas in the only other report in thyrocytes regarding c-jun, TSH in the presence of cycloheximide inhibited TPA-induced c-jun mRNA in canine thyrocytes (8), as also noted in mouse fibroblasts for PKA-TPA interactions (21), but unlike our data in human thyrocytes. Regarding the effects of TSH/PKA on the EGF/tyrosine kinase pathway in thyroid cells, TSH inhibited IGF-I-induced c-jun mRNA in WRT cells (9), in agreement with our observations, but in canine thyrocytes, unlike our data in thyrocytes of human origin, TSH in the presence of cycloheximide inhibited EGF-induced c-jun mRNA (8). With regard to c-fos mRNA, except for WRT cells showing a TSH inhibitory effect on IGF-I-induced c-fos mRNA (9) similar to our results, other reports on thyrocytes noted an additive or synergistic effect between the two pathways: TSH and EGF in canine thyrocytes (12), TSH and IGF-I/insulin in FRTL-5 cells (14), and TSH and insulin in human fetal thyroid monolayer cells (19). The requirement for protein synthesis for the inhibitory effect of TSH (PKA) on TPA (PKC)- and EGF (tyrosine kinase)-induced c-fos mRNA has not been previously reported in thyroid cells.

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 those in our previous study on cell growth and differentiation (2), we found the TSH/PKA pathway to inhibit PKC- and EGF/tyrosine kinase-induced c-jun and c-fos mRNA, i.e. parallel antagonistic effects as previously observed measuring cell proliferation. The findings suggest an association between human thyroid cell proliferation and c-jun and c-fos gene expression.


   Footnotes
 
1 Presented in part at the 11th International Thyroid Congress, Toronto, Canada, September 1995 (Abstract 406). This work was supported by the L. Stoll Switzer Cancer Research Fund. Back

Received October 24, 1996.

Revised February 5, 1997.

Accepted March 7, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Kraiem Z, Sadeh O, Yosef M. 1991 Iodide uptake and organification, tri-iodothyronine secretion, cyclic AMP accumulation and cell proliferation in an optimized system of human thyroid follicles cultured in collagen gel suspended in serum free medium. J Endocrinol. 131:499–506.[Abstract/Free Full Text]
  2. Kraiem Z, Sadeh O, Yosef M, Aharon A. 1995 Mutual antagonistic interactions between the thyrotropin (adenosine 3',5'-monophosphate) and protein kinase C/epidermal growth factor (tyrosine kinase) pathways in cell proliferation and differentiation of cultured human thyroid follicles. Endocrinology. 136:585–590.[Abstract]
  3. Roger PP, Reuse S, Maenhaut C, Dumont JE. 1995 Multiple facets of the modulation of growth by cAMP. Vitam Horm. 51:59–191.[Medline]
  4. Angel P, Karin M. 1991 The role of Jun, Fos and the AP-1 complex in cell proliferation and transformation. Biochim Biophys Acta 1072:129–157.
  5. Edwards DR, Mahadevan LC. 1992 Protein synthesis inhibitors differentially superinduce c-fos and c-jun by three distinct mechanisms: lack of evidence for labile repressors. EMBO J. 11:2415–2424.[Medline]
  6. Eggo MC. 1993 Protein kinase C in the thyroid. J Endocrinol. 138:1–5.[Abstract/Free Full Text]
  7. Colletta G, Cirafici AM. 1992 TSH is able to induce cell-cycle related gene expression in rat thyroid cells. Biochem Biophys Res Commun. 183:265–272.[CrossRef][Medline]
  8. Reuse S, Pirson I, Dumont JE. 1991 Differential regulation of proto-oncogenes c-jun and jun D expressions by protein tyrosine kinase, protein kinase C, and cyclic-AMP mitogenic pathways in dog primary thyrocytes: TSH and cyclic-AMP induce proliferation but downregulate c-jun expression. Exp Cell Res. 196:210–215.[CrossRef][Medline]
  9. Tominaga T, Dela Cruz J, Burrow GN, Meinkoth JL. 1994 Divergent patterns of immediate early gene expression in response to thyroid-stimulating hormone and insulin-like growth factor I in Wistar rat thyrocytes. Endocrinology. 135:1212–1219.[Abstract]
  10. Kambe F, Miyazaki T, Seo H. 1996 Differential induction of fos and jun family genes by thyrotropin in rat thyroid FRTL-5 cells. Thyroid. 6:123–128.[Medline]
  11. Heldin NE, Westermark B. 1988 Epidermal growth factor, but not thyrotropin, stimulates the expression of c-fos and c-myc messenger ribonucleic acid in porcine thyroid follicle cells in primary culture. Endocrinology. 122:1042–1046.[Abstract]
  12. Reuse S, Maenhaut C, Dumont JE. 1990 Regulation of proto-oncogenes c-fos and c-myc expressions by protein tyrosine kinase, protein kinase C, and cyclic AMP mitogenic pathways in dog primary thyrocytes: a positive and negative control by cyclic AMP on c-myc expression. Exp Cell Res. 189:33–40.[CrossRef][Medline]
  13. Raspe E, Reuse S, Roger PP, Dumont JE. 1992 Lack of correlation between the activation of the Ca++-phosphatidylinositol cascade and the regulation of DNA synthesis in the dog thyrocyte. Exp Cell Res. 198:17–26.[CrossRef][Medline]
  14. Isozaki O, Kohn LD. 1987 Control of c-fos and c-myc proto-oncogene induction in rat thyroid cells in culture. Mol Endocrinol. 1:839–848.[CrossRef][Medline]
  15. Isozaki O, Emoto N, Tsushima T, et al. 1992 Opposite regulation of deoxyribonucleic acid synthesis and iodide uptake in rat thyroid cells by basic fibroblast growth factor: correlation with opposite regulation of c-fos and thyrotropin receptor gene expression. Endocrinology. 131:2723–2732.[Abstract]
  16. Tramontano D, Chin WW, Moses AC, Ingbar SH. 1986 Thyrotropin and dibutyryl cyclic AMP increase levels of c-myc and c-fos mRNA in cultured rat thyroid cells. J Biol Chem. 261:3919–3922.[Abstract/Free Full Text]
  17. Colletta G, Cirafici AM, Vecchio G. 1986 Induction of the c-fos oncogene by thyrotropic hormone in rat thyroid cells in culture. Science. 233:458–460.[Abstract/Free Full Text]
  18. Damante G, Rapoport B. 1988 TSH stimulates the activity of the c-fos promoter in FRTL5 rat thyroid cells. Mol Cell Endocrinol. 58:279–282.[CrossRef][Medline]
  19. Huber GK, Safirstein R, Neufeld D, Davies TF. 1991 Thyrotropin receptor autoantibodies induce human thyroid cell growth and c-fos activation. J Clin Endocrinol Metab. 72:1142–1147.[Abstract]
  20. Chiu R, Angel P, Karin M. 1989 Jun-B differs in its biological properties from, and is a negative regulator of, c-Jun. Cell. 59:979–986.[CrossRef][Medline]
  21. Mechta F, Piette J, Hirai SI, Yaniv M. 1989 Stimulation of protein kinase C or protein kinase A mediated signal transduction pathways shows three modes of response among serum inducible genes. New Biol. 1:297–304.[Medline]
  22. Tamir A, Isakov N. 1991 Increased intracellular cyclic AMP levels block PKC-mediated T cell activation by inhibition of c-jun transcription. Immunol Lett. 27:95–100.[CrossRef][Medline]



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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.
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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.
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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.
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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.
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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.
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