Abstract
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor of the calcitonin secreting thyroid C-cells. Somatic and germline mutations in the RET proto-oncogene are associated with sporadic and inherited cases of MTC, respectively. The human MTC cell line, TT, can be differentiated by activated raf-1. This differentiation is characterized, in part, by down-regulation of the RET proto-oncogene. We now show that raf-1 induction is followed by activation of the downstream kinases MEK1/2 and ERK1/2 and that differentiation is dependent on activation of MEK1/2. The concurrent down-regulation of RET appears to involve altered nuclear compartmentalization and transport of RET mRNA. Although RET is down-regulated during raf-1 mediated differentiation, overexpression of activated RET alleles which resist down-regulation does not alter the raf-1 mediated differentiation response. These data suggest that RET down-regulation is associated with, but not required, for raf-1 mediated MTC cell differentiation and that the raf-1 signal transduction pathway plays a dominant role in promoting MTC cell differentiation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Carcinoma, Medullary
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Cell Differentiation
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Cell Division
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Cell Line
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Cell Nucleus / metabolism
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Dactinomycin / pharmacology
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Drosophila Proteins*
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Estradiol / pharmacology
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Ethanol / pharmacology
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Gene Expression Regulation, Neoplastic* / drug effects
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Humans
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Kinetics
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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Mitogen-Activated Protein Kinase Kinases*
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Protein Serine-Threonine Kinases / metabolism
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Protein-Tyrosine Kinases / metabolism
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Proto-Oncogene Mas
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Proto-Oncogene Proteins / biosynthesis*
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Proto-Oncogene Proteins c-raf / metabolism*
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Proto-Oncogene Proteins c-ret
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Proto-Oncogenes*
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Receptor Protein-Tyrosine Kinases / biosynthesis*
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Thyroid Neoplasms
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Tumor Cells, Cultured
Substances
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Drosophila Proteins
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MAS1 protein, human
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Proto-Oncogene Mas
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Proto-Oncogene Proteins
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Dactinomycin
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Ethanol
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Estradiol
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MAP2K2 protein, human
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-ret
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases
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MAP Kinase Kinase 1
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MAP Kinase Kinase 2
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MAP2K1 protein, human
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Mitogen-Activated Protein Kinase Kinases