Abstract
RET gene rearrangements, which generate chimeric RET/PTC oncogenes, are early events in the evolution of thyroid papillary carcinomas. Expression of RET/PTC oncogenes promotes neoplastic transformation of cultured thyroid cells and of thyroid glands in transgenic mice. Notwithstanding these oncogenic effects, we have found that the expression of two RET/PTC oncogenes (H4-RET and RFG-RET) induces apoptosis of rat thyroid PC CL 3 cells. Promotion of thyroid cell death depends on the kinase activity of RET/PTC and on the phosphorylation of a tyrosine residue (tyrosine 1062) that maps in the carboxy-terminus of the RET protein. Tyrosine 1062 is essential for RET/PTC-mediated activation of the Ras/ERK pathway. Inhibition of Ras/ERK by a dominant negative Ras or by the MEKI inhibitor, PD98059, obstructed RET/PTC-mediated apoptosis. We also show that signals transmitted by tyrosine 1062 mediate proapoptotic events like Bcl-2 down regulation and Bax upregulation, and that adoptive overexpression of Bcl-2 overcomes RET/PTC-induced apoptosis. Thus, gene rearrangements that generate RET/PTC oncogenes subvert RET function by converting it into a chronically active kinase that is constitutively phosphorylated on tyrosine 1062. In turn, Y1062 phosphorylation transmits not only mitogenic but also proapoptotic signals to thyroid cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / physiology*
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Cell Differentiation / physiology
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Cells, Cultured
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Drosophila Proteins*
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Enzyme Inhibitors / pharmacology
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Feedback, Physiological
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Flavonoids / pharmacology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Oncogene Proteins / genetics
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Oncogene Proteins / metabolism*
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Oncogene Proteins, Fusion
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Phosphoprotein Phosphatases / genetics
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Phosphoprotein Phosphatases / metabolism
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Protein Phosphatase 2
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Protein Phosphatase 2C
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Proto-Oncogene Proteins c-ret
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Rats
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Rats, Inbred F344
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Saccharomyces cerevisiae Proteins*
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Signal Transduction
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Thyroid Gland / pathology*
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Thyroid Gland / physiology
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Tyrosine / metabolism
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Up-Regulation
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bcl-2-Associated X Protein
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ras Proteins / genetics
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ras Proteins / metabolism*
Substances
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Bax protein, rat
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Drosophila Proteins
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Enzyme Inhibitors
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Flavonoids
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Oncogene Proteins
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Oncogene Proteins, Fusion
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Proto-Oncogene Proteins
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Proto-Oncogene Proteins c-bcl-2
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Recombinant Proteins
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Saccharomyces cerevisiae Proteins
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bcl-2-Associated X Protein
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Tyrosine
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Protein-Tyrosine Kinases
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Proto-Oncogene Proteins c-ret
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RET-PTC oncoprotein, rat
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Receptor Protein-Tyrosine Kinases
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Ret protein, Drosophila
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Ret protein, rat
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Ret-Ptc1 oncoprotein, mouse
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Mitogen-Activated Protein Kinases
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PTC1 protein, S cerevisiae
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Phosphoprotein Phosphatases
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Protein Phosphatase 2
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Protein Phosphatase 2C
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ras Proteins
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one