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.

Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes / M. D., Castellone; A. M., Cirafici; DE VITA, Gabriella; V. D., Falco; L., Malorni; G., Tallini; J. A., Fagin; Fusco, Alfredo; Melillo, ROSA MARINA; M., Santoro. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 22:(2003), pp. 246-255. [10.1038/sj.onc.1206112]

Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes

DE VITA, GABRIELLA;FUSCO, ALFREDO;MELILLO, ROSA MARINA;
2003

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.
2003
Ras-mediated apoptosis of PC CL 3 rat thyroid cells induced by RET/PTC oncogenes / M. D., Castellone; A. M., Cirafici; DE VITA, Gabriella; V. D., Falco; L., Malorni; G., Tallini; J. A., Fagin; Fusco, Alfredo; Melillo, ROSA MARINA; M., Santoro. - In: ONCOGENE. - ISSN 0950-9232. - STAMPA. - 22:(2003), pp. 246-255. [10.1038/sj.onc.1206112]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/463024
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