title: Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes.
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.
authors.affiliation: Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia, University Federico II, Naples, Italy.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Castellone
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Cirafici
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Vita
authors.forename: Valentina
authors.initials: V
authors.lastname: De Falco
authors.forename: Luca
authors.initials: L
authors.lastname: Malorni
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tallini
authors.forename: James A
authors.initials: JA
authors.lastname: Fagin
authors.forename: Alfredo
authors.initials: A
authors.lastname: Fusco
authors.forename: Rosa Marina
authors.initials: RM
authors.lastname: Melillo
authors.forename: Massimo
authors.initials: M
authors.lastname: Santoro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological; D005419:Flavonoids / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051096:Proto-Oncogene Proteins c-ret; D051381:Rats; D011916:Rats, Inbred F344; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins; D015398:Signal Transduction; D013961:Thyroid Gland / Q000473:pathology* / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C494828:Bax protein, rat; D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D015513:Oncogene Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; D051028:bcl-2-Associated X Protein; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D051096:Proto-Oncogene Proteins c-ret; C490558:RET-PTC oncoprotein, rat; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila; C495001:Ret protein, rat; C490559:Ret-Ptc1 oncoprotein, mouse; D020928:Mitogen-Activated Protein Kinases; C087358:PTC1 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one