Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes.
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.
Castellone
Maria Domenica
MD
Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, c/o Dipartimento di Biologia, University Federico II, Naples, Italy.
Cirafici
Anna Maria
AM
De Vita
Gabriella
G
De Falco
Valentina
V
Malorni
Luca
L
Tallini
Giovanni
G
Fagin
James A
JA
Fusco
Alfredo
A
Melillo
Rosa Marina
RM
Santoro
Massimo
M
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*
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