| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Division of Endocrinology and Metabolism (J.W., J.A.K., S.B., E.P., H.K., J.A.F.), University of Cincinnati College of Medicine, Cincinnati, Ohio 45267; and Istituto di Endocrinologia ed Oncologia Sperimentale (M.S., A.F.), Consiglio Nazionale delle Ricerche c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, University "Federico II," Naples, Italy
Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, P.O. Box 670547, Cincinnati, Ohio 45267-0547. E-mail: James.Fagin{at}uc.edu.
Chromosomal rearrangements linking the promoter(s) and N-terminal domain of unrelated gene(s) to the C terminus of RET result in constitutively activated chimeric forms of the receptor in thyroid cells (RET/PTC). RET/PTC rearrangements are thought to be tumor-initiating events; however, the early biological consequences of RET/PTC activation are unknown. To explore this, we generated clonal lines derived from well-differentiated rat thyroid PCCL3 cells with doxycycline-inducible expression of either RET/PTC1 or RET/PTC3. As previously shown in other cell types, RET/PTC1 and RET/PTC3 oligomerized and displayed constitutive tyrosine kinase activity. Neither RET/PTC1 nor RET/PTC3 conferred cells with the ability to grow in the absence of TSH, likely because of concomitant stimulation of both DNA synthesis and apoptosis, resulting in no net growth in the cell population. Effects of RET/PTC on DNA synthesis and apoptosis did not require direct interaction of the oncoprotein with either Shc or phospholipase C
. Acute expression of the oncoprotein decreased TSH-mediated growth stimulation due to interference of TSH signaling by RET/PTC at multiple levels. Taken together, these data indicate that RET/PTC is a weak tumor-initiating event and that TSH action is disrupted by this oncoprotein at several points, and also predict that secondary genetic or epigenetic changes are required for clonal expansion.
This article has been cited by other articles:
 |
|
 |
|
  G. Riesco-Eizaguirre and P. Santisteban New insights in thyroid follicular cell biology and its impact in thyroid cancer therapy Endocr. Relat. Cancer, December 1, 2007; 14(4): 957 - 977. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Xing BRAF Mutation in Papillary Thyroid Cancer: Pathogenic Role, Molecular Bases, and Clinical Implications Endocr. Rev., December 1, 2007; 28(7): 742 - 762. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Santoro, R. M. Melillo, and A. Fusco RET/PTC activation in papillary thyroid carcinoma: European Journal of Endocrinology Prize Lecture. Eur. J. Endocrinol., November 1, 2006; 155(5): 645 - 653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Knauf, B. Ouyang, E. S. Knudsen, K. Fukasawa, G. Babcock, and J. A. Fagin Oncogenic RAS Induces Accelerated Transition through G2/M and Promotes Defects in the G2 DNA Damage and Mitotic Spindle Checkpoints J. Biol. Chem., February 17, 2006; 281(7): 3800 - 3809. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mitsutake, M. Miyagishi, S. Mitsutake, N. Akeno, C. Mesa Jr, J. A. Knauf, L. Zhang, K. Taira, and J. A. Fagin BRAF Mediates RET/PTC-Induced Mitogen-Activated Protein Kinase Activation in Thyroid Cells: Functional Support for Requirement of the RET/PTC-RAS-BRAF Pathway in Papillary Thyroid Carcinogenesis Endocrinology, February 1, 2006; 147(2): 1014 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. E. Santiago-Walker, A. J. Fikaris, G. D. Kao, E. J. Brown, M. G. Kazanietz, and J. L. Meinkoth Protein Kinase C {delta} Stimulates Apoptosis by Initiating G1 Phase Cell Cycle Progression and S Phase Arrest J. Biol. Chem., September 16, 2005; 280(37): 32107 - 32114. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E Puxeddu, J A Knauf, M A Sartor, N Mitsutake, E P Smith, M Medvedovic, C R Tomlinson, S Moretti, and J A Fagin RET/PTC-induced gene expression in thyroid PCCL3 cells reveals early activation of genes involved in regulation of the immune response Endocr. Relat. Cancer, June 1, 2005; 12(2): 319 - 334. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Mitsutake, J. A. Knauf, S. Mitsutake, C. Mesa Jr., L. Zhang, and J. A. Fagin Conditional BRAFV600E Expression Induces DNA Synthesis, Apoptosis, Dedifferentiation, and Chromosomal Instability in Thyroid PCCL3 Cells Cancer Res., March 15, 2005; 65(6): 2465 - 2473. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Venkateswaran, D. K. Marsee, S. H. Green, and S. M. Jhiang Forskolin, 8-Br-3',5'-Cyclic Adenosine 5'-Monophosphate, and Catalytic Protein Kinase A Expression in the Nucleus Increase Radioiodide Uptake and Sodium/Iodide Symporter Protein Levels in RET/PTC1-Expressing Cells J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6168 - 6172. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. S. Hwang, D. W. Kim, J. H. Hwang, H. S. Jung, J. M. Suh, Y. J. Park, H. K. Chung, J. H. Song, K. C. Park, S. H. Park, et al. Regulation of Signal Transducer and Activator of Transcription 1 (STAT1) and STAT1-Dependent Genes by RET/PTC (Rearranged in Transformation/Papillary Thyroid Carcinoma) Oncogenic Tyrosine Kinases Mol. Endocrinol., November 1, 2004; 18(11): 2672 - 2684. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Puxeddu, N. Mitsutake, J. A. Knauf, S. Moretti, H. W. Kim, K. A. Seta, D. Brockman, L. Myatt, D. E. Millhorn, and J. A. Fagin Microsomal Prostaglandin E2 Synthase-1 Is Induced by Conditional Expression of RET/PTC in Thyroid PCCL3 Cells through the Activation of the MEK-ERK Pathway J. Biol. Chem., December 26, 2003; 278(52): 52131 - 52138. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
