This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by al-Alawi, N. Articles by Feramisco, J. R. Search for Related Content PubMed PubMed Citation Articles by al-Alawi, N. Articles by Feramisco, J. R.

 Previous Article  |  Next Article 

Mol. Cell. Biol., 03 1995, 1162-1168, Vol 15, No. 3
Copyright © 1995, American Society for Microbiology

Thyrotropin-induced mitogenesis is Ras dependent but appears to bypass the Raf-dependent cytoplasmic kinase cascade

N al-Alawi, DW Rose, C Buckmaster, N Ahn, U Rapp, J Meinkoth and JR Feramisco
Department of Pharmacology, University of California at San Diego, La Jolla 92093.

Cellular growth control requires the coordination and integration of multiple signaling pathways which are likely to be activated concomitantly. Mitogenic signaling initiated by thyrotropin (TSH) in thyroid cells seems to require two distinct signaling pathways, a cyclic AMP (cAMP)-dependent signaling pathway and a Ras-dependent pathway. This is a paradox, since activated cAMP-dependent protein kinase disrupts Ras-dependent signaling induced by growth factors such as epidermal growth factor and platelet-derived growth factor. This inhibition may occur by preventing Raf-1 protein kinase from binding to Ras, an event thought to be necessary for the activation of Raf-1 and the subsequent activation of the mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinases (MEKs) and MAP kinase (MAPK)/ERKs. Here we report that serum-stimulated hyperphosphorylation of Raf-1 was inhibited by TSH treatment of Wistar rat thyroid cells, indicating that in this cell line, as in other cell types, increases in intracellular cAMP levels inhibit activation of downstream kinases targeted by Ras. Ras-stimulated expression of genes containing AP-1 promoter elements was similarly inhibited by TSH. On the other hand, stimulation of thyroid cells with TSH resulted in stimulation of DNA synthesis which was Ras dependent but both Raf-1 and MEK independent. We also show that Ras-stimulated DNA synthesis required the use of this kinase cascade in untreated quiescent cells but not in TSH-treated cells. These data suggest that in TSH-treated thyroid cells, Ras might be able to signal through effectors other than the well-studied cytoplasmic kinase cascade.

This article has been cited by other articles:

• Zaballos, M. A., Garcia, B., Santisteban, P. (2008). G{beta}{gamma} Dimers Released in Response to Thyrotropin Activate Phosphoinositide 3-Kinase and Regulate Gene Expression in Thyroid Cells. Mol. Endocrinol. 22: 1183-1199 [Abstract] [Full Text]  
• Wayne, C. M., Fan, H.-Y., Cheng, X., Richards, J. S. (2007). Follicle-Stimulating Hormone Induces Multiple Signaling Cascades: Evidence that Activation of Rous Sarcoma Oncogene, RAS, and the Epidermal Growth Factor Receptor Are Critical for Granulosa Cell Differentiation. Mol. Endocrinol. 21: 1940-1957 [Abstract] [Full Text]  
• Needle, E., Piparo, K., Cole, D., Worrall, C., Whitehead, I., Mahon, G., Goldsmith, L. T. (2007). Protein Kinase A-Independent cAMP Stimulation of Progesterone in a Luteal Cell Model Is Tyrosine Kinase Dependent but Phosphatidylinositol-3-Kinase and Mitogen-Activated Protein Kinase Independent. Biol. Reprod. 77: 147-155 [Abstract] [Full Text]  
• Vadysirisack, D. D, Venkateswaran, A., Zhang, Z., Jhiang, S. M (2007). MEK signaling modulates sodium iodide symporter at multiple levels and in a paradoxical manner. Endocr Relat Cancer 14: 421-432 [Abstract] [Full Text]  
• Abulaiti, A., Fikaris, A. J., Tsygankova, O. M., Meinkoth, J. L. (2006). Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response. Cancer Res. 66: 10505-10512 [Abstract] [Full Text]  
• Illario, M., Cavallo, A. L., Monaco, S., Di Vito, E., Mueller, F., Marzano, L. A., Troncone, G., Fenzi, G., Rossi, G., Vitale, M. (2005). Fibronectin-Induced Proliferation in Thyroid Cells Is Mediated by {alpha}v{beta}3 Integrin through Ras/Raf-1/MEK/ERK and Calcium/CaMKII Signals. J. Clin. Endocrinol. Metab. 90: 2865-2873 [Abstract] [Full Text]  
• Cheng, G., Lewis, A. E., Meinkoth, J. L. (2003). Ras Stimulates Aberrant Cell Cycle Progression and Apoptosis in Rat Thyroid Cells. Mol. Endocrinol. 17: 450-459 [Abstract] [Full Text]  
• Dohan, O., De la Vieja, A., Paroder, V., Riedel, C., Artani, M., Reed, M., Ginter, C. S., Carrasco, N. (2003). The Sodium/Iodide Symporter (NIS): Characterization, Regulation, and Medical Significance. Endocr. Rev. 24: 48-77 [Abstract] [Full Text]  
• Ribeiro-Neto, F., Urbani, J., Lemee, N., Lou, L., Altschuler, D. L. (2002). On the mitogenic properties of Rap1b: cAMP-induced G1/S entry requires activated and phosphorylated Rap1b. Proc. Natl. Acad. Sci. USA 99: 5418-5423 [Abstract] [Full Text]  
• Iacovelli, L., Capobianco, L., Salvatore, L., Sallese, M., D'Ancona, G. M., De Blasi, A. (2001). Thyrotropin Activates Mitogen-Activated Protein Kinase Pathway in FRTL-5 by a cAMP-Dependent Protein Kinase A-Independent Mechanism. Mol. Pharmacol. 60: 924-933 [Abstract] [Full Text]  
• Kimura, T., Van Keymeulen, A., Golstein, J., Fusco, A., Dumont, J. E., Roger, P. P. (2001). Regulation of Thyroid Cell Proliferation by TSH and Other Factors: A Critical Evaluation of in Vitro Models. Endocr. Rev. 22: 631-656 [Abstract] [Full Text]  
• Richards, J. S. (2001). New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells. Mol. Endocrinol. 15: 209-218 [Abstract] [Full Text]  
• Pombo, C. M., Zalvide, J., Gaylinn, B. D., Dieguez, C. (2000). Growth Hormone-Releasing Hormone Stimulates Mitogen-Activated Protein Kinase. Endocrinology 141: 2113-2119 [Abstract] [Full Text]  
• Genersch, E, Hayess, K, Neuenfeld, Y, Haller, H (2000). Sustained ERK phosphorylation is necessary but not sufficient for MMP-9 regulation in endothelial cells: involvement of Ras-dependent and -independent pathways. J. Cell Sci. 113: 4319-4330 [Abstract]  
• Derwahl, M., Broecker, M., Kraiem, Z. (1999). Thyrotropin May Not Be the Dominant Growth Factor in Benign and Malignant Thyroid Tumors. J. Clin. Endocrinol. Metab. 84: 829-834 [Full Text]  
• Tang, Y., Yu, J., Field, J. (1999). Signals from the Ras, Rac, and Rho GTPases Converge on the Pak Protein Kinase in Rat-1 Fibroblasts. Mol. Cell. Biol. 19: 1881-1891 [Abstract] [Full Text]  
• Miller, M. J., Rioux, L., Prendergast, G. V., Cannon, S., White, M. A., Meinkoth, J. L. (1998). Differential Effects of Protein Kinase A on Ras Effector Pathways. Mol. Cell. Biol. 18: 3718-3726 [Abstract] [Full Text]  
• Cass, L. A., Meinkoth, J. L. (1998). Differential Effects of Cyclic Adenosine 3',5'-Monophosphate on p70 Ribosomal S6 Kinase. Endocrinology 139: 1991-1998 [Abstract] [Full Text]  
• Miller, M. J., Prigent, S., Kupperman, E., Rioux, L., Park, S.-H., Feramisco, J. R., White, M. A., Rutkowski, J. L., Meinkoth, J. L. (1997). RalGDS Functions in Ras- and cAMP-mediated Growth Stimulation. J. Biol. Chem. 272: 5600-5605 [Abstract] [Full Text]  
• Feliciello, A., Giuliano, P., Porcellini, A., Garbi, C., Obici, S., Mele, E., Angotti, E., Grieco, D., Amabile, G., Cassano, S., Li, Y., Musti, A. M., Rubin, C. S., Gottesman, M. E., V. Avvedimento, E. (1996). The v-Ki-Ras Oncogene Alters cAMP Nuclear Signaling by Regulating the Location and the Expression of cAMP-dependent Protein Kinase IIbeta. J. Biol. Chem. 271: 25350-25359 [Abstract] [Full Text]  
• McKenzie, F. R., Pouyssegur, J. (1996). cAMP-mediated Growth Inhibition in Fibroblasts Is Not Mediated via Mitogen-activated Protein (MAP) Kinase (ERK) Inhibition. cAMP-DEPENDENT PROTEIN KINASE INDUCES A TEMPORAL SHIFT IN GROWTH FACTOR-STIMULATED MAP KINASES. J. Biol. Chem. 271: 13476-13483 [Abstract] [Full Text]  
• Gum, R., Lengyel, E., Juarez, J., Chen, J. H., Sato, H., Seiki, M., Boyd, D. (1996). Stimulation of 92-kDa Gelatinase B Promoter Activity by ras Is Mitogen-activated Protein Kinase Kinase 1-independent and Requires Multiple Transcription Factor Binding Sites Including Closely Spaced PEA3/ets and AP-1 Sequences. J. Biol. Chem. 271: 10672-10680 [Abstract] [Full Text]  
• Lengyel, E., Stepp, E., Gum, R., Boyd, D. (1995). Involvement of a Mitogen-activated Protein Kinase Signaling Pathway in the Regulation of Urokinase Promoter Activity by c-Ha-ras. J. Biol. Chem. 270: 23007-23012 [Abstract] [Full Text]