Abstract
RET/papillary thyroid carcinoma (PTC), TRK-T, or activating mutations of Ras and BRaf are frequent genetic alterations in PTC, all leading to the activation of the extracellular-regulated kinase (Erk) cascade. The aim of this study was to investigate the role of calmodulin-dependent kinase II (CaMKII) in the signal transduction leading to Erk activation in PTC cells. In normal thyroid cells, CaMKII and Erk were in the inactive form in the absence of stimulation. In primary PTC cultures and in PTC cell lines harboring the oncogenes RET/PTC-1 or BRaf(V600E), CaMKII was active also in the absence of any stimulation. Inhibition of calmodulin or phospholipase C (PLC) attenuated the level of CaMKII activation. Expression of recombinant RET/PTC-3, BRaf(V600E), or Ras(V12) induced CaMKII activation. Inhibition of CaMKII attenuated Erk activation and DNA synthesis in thyroid papillary carcinoma (TPC-1), a cell line harboring RET/PTC-1, suggesting that CaMKII is a component of the Erk signal cascade in this cell line. In conclusion, PTCs contain an active PLC/Ca(2+)/calmodulin-dependent signal inducing constitutive activation of CaMKII. This kinase is activated by BRaf(V600E), oncogenic Ras, and by RET/PTC. CaMKII participates to the activation of the Erk pathway by oncogenic Ras and RET/PTC and contributes to their signal output, thus modulating tumor cell proliferation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Calcium Signaling / physiology
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / physiology*
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Calmodulin / physiology
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Carcinoma, Papillary / enzymology*
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Carcinoma, Papillary / genetics
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Carcinoma, Papillary / pathology
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Cell Division
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Enzyme Activation / drug effects
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Estrenes / pharmacology
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Extracellular Signal-Regulated MAP Kinases / physiology*
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Humans
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / physiology
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Molecular Sequence Data
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Mutation
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology*
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Oncogene Protein p21(ras) / physiology
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Piperidines / pharmacology
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / physiology
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Proto-Oncogene Proteins c-ret / physiology
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Pyrrolidinones / pharmacology
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Quinazolines / pharmacology
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Rats
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Thyroid Neoplasms / enzymology*
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / pathology
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Type C Phospholipases / physiology
Substances
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Calmodulin
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Estrenes
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Neoplasm Proteins
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Piperidines
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Protein Kinase Inhibitors
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Pyrrolidinones
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Quinazolines
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1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione
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Proto-Oncogene Proteins c-ret
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Extracellular Signal-Regulated MAP Kinases
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Type C Phospholipases
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Oncogene Protein p21(ras)
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vandetanib