One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes.

Fusco, A.; Berlingieri, Maria Teresa; Fiore, Pier Paolo Di; Portella, Giuseppe; Grieco, Michèle; Vecchio, G.

doi:10.1128/mcb.7.9.3365

Cited by 229 publications

(249 citation statements)

References 11 publications

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“…Although the mitogenic activity of TSH is Ras-dependent (Kupperman et al, 1993), oncogenic Ras impairs the ability of TSH to stimulate thyroid-speci®c gene expression. De-di erentiation occurs in Ras-transformed thyroid cells (Fusco et al, 1987;Avvedimento et al, 1989) and in cells acutely injected with Ras proteins (Kupperman et al, 1996), indicating that even transient expression of activated Ras induces de-di erentiation. We sought to determine how Ras mediates the mitogenic e ects of TSH in a manner that allows for maintenance of the di erentiated phenotype.…”

Section: Discussionmentioning

confidence: 99%

“…In Wistar rat thyroid (WRT) cells, the mitogenic activity of TSH is Ras-dependent, and the requirement for Ras maps downstream from cAMP (Kupperman et al, 1993). Expression of oncogenic Hor K-Ras in thyroid cells confers TSH-independent proliferation (Fusco et al, 1987;Lemoine et al, 1990;Meinkoth et al, 1991), and mutations in all three cellular Ras genes have been identi®ed in human thyroid tumors (Fagin, 1994). While Ras stimulates thyroid cell proliferation, Ras transformation leads to decreased expression and/or activity of the transcription factors TTF-1 and TTF-2, resulting in the loss of thyroid-speci®c gene expression (Fusco et al, 1987;Avvedimento et al, 1989;Francis-Lang et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

“…Expression of oncogenic Hor K-Ras in thyroid cells confers TSH-independent proliferation (Fusco et al, 1987;Lemoine et al, 1990;Meinkoth et al, 1991), and mutations in all three cellular Ras genes have been identi®ed in human thyroid tumors (Fagin, 1994). While Ras stimulates thyroid cell proliferation, Ras transformation leads to decreased expression and/or activity of the transcription factors TTF-1 and TTF-2, resulting in the loss of thyroid-speci®c gene expression (Fusco et al, 1987;Avvedimento et al, 1989;Francis-Lang et al, 1992). Nonetheless, Ras mutations are found in hyperfunctioning adenomas and in di erentiated follicular and papillary carcinomas (Wynford-Thomas, 1997), evidence that expression of activated Ras is not invariably associated with thyroid de-di erentiation.…”

Section: Introductionmentioning

confidence: 99%

“…Alterations in the balance of the activity of these pathways may contribute to the di erential cellular responses elicited by Ras. Multiple Ras-dependent pathways converge in the regulation of di erentiation and cell cycle arrest in PC12 cells, where the e ects of Ras on neurite extension and growth arrest are mimicked by Raf-1 and PI3K, while RalGDS inhibits withdrawal from the cell cycle (Goi et al, 1999). In thyroid cells, cAMP impairs Ras signaling through Raf-1 (Al-Alawi et al, 1995) and augments Ras signaling through RalGDS (Miller et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

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Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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Hormones are specialized mitogens that stimulate proliferation in their di erentiated target cells. Thyrotropin (TSH), the physiologic regulator of thyroid cells, stimulates cAMP-mediated proliferation and thyroidspeci®c gene expression. The mitogenic e ects of TSH require Ras, therefore Ras activation should be compatible with the maintenance of thyroid di erentiation. However, expression of activated Ras extinguishes the di erentiated phenotype of thyroid cells. One explanation for this apparent paradox is the selective utilization of Ras e ector pathways. We tested the hypothesis that Ras signaling through PI3K mediates the mitogenic e ects of TSH in cells which retain their di erentiated character. Expression of a Ras e ector mutant (RasV12S35) that signals preferentially through Raf-1, although su cient to confer TSH-independent proliferation, abolished hormone-regulated expression of thyroglobulin and the sodium/iodide symporter. In contrast, expression of a Ras mutant (RasV12C40) that binds selectively to PI3K conferred TSH-independent proliferation without marked e ects on thyroid-speci®c gene expression. Unlike the inhibitory e ects of TSH on the proliferation of RasV12S35-expressing cells, TSH enhanced RasV12C40-stimulated proliferation by further increasing the activity of p70s6k, an important mediator of the mitogenic e ects of TSH and RasV12C40. These results demonstrate that channeling Ras-dependent signals to PI3K confers TSH with the ability to stimulate proliferation in di erentiated cells. Oncogene (2000) 19, 924 ± 932.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Cass

Meinkoth

2000

Oncogene

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“…PC12 cells were grown in RPMI 1640 medium supplemented with 10% horse serum and 5% foetal calf serum (GIBCO-BRL). The PC Cl 3, thyroid epithelial cell line, was cultured in modi®ed F12 medium, supplemented with 5% calf serum (GIBCO-BRL) and six growth factors (thyrotropin, hydrocortisone, insulin, transferrin, somatostatin and glycil-histidyl-lysine) (SIGMA Chemical Corporation) (Fusco et al, 1987). Stable transfectants of the thryoid (Santoro et al, 1993) and NIH3T3 cells Carlomagno et al, 1996) with the RET mutants have been described.…”

Section: Cell Culture and Transfection Experimentsmentioning

confidence: 99%

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

et al. 1998

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The RET proto-oncogene encodes a functional receptor tyrosine kinase (Ret) for the Glial cell line Derived Neurotrophic Factor (GDNF). RET is involved in several neoplastic and non-neoplastic human diseases. Oncogenic activation of RET is detected in human papillary thyroid tumours and in multiple endocrine neoplasia type 2 syndromes. Inactivating mutations of RET have been associated to the congenital megacolon, i.e. Hirschprung's disease. In order to identify pathways that are relevant for Ret signalling to the nucleus, we have investigated its ability to induce the c-Jun NH 2 -terminal protein kinases (JNK). Here we show that triggering the endogenous Ret, expressed in PC12 cells, induces JNK activity; moreover, Ret is able to activate JNK either when transiently transfected in COS-1 cells or when stably expressed in NIH3T3 ®broblasts or in PC Cl 3 epithelial thyroid cells. JNK activation is dependent on the Ret kinase function, as a kinase-de®cient RET mutant, associated with Hirschsprung's disease, fails to activate JNK. The pathway leading to the activation of JNK by RET is clearly divergent from that leading to the activation of ERK: substitution of the tyrosine 1062 of Ret, the Shc binding site, for phenylalanine abrogates ERK but not JNK activation. Experiments conducted with dominant negative mutants or with negative regulators demonstrate that JNK activation by Ret is mediated by Rho/Rac related small GTPases and, particularly, by Cdc42.

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Changes in in vitro growth behaviour of the mammary epithelial cell line NMuMG caused by the v‐fos oncogene

Bradbury

Edwards

1988

Intl Journal of Cancer

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A defective retrovirus was constructed to investigate the effect of the expression of the v‐fos oncogene from FBJ‐MSV on the in vitro growth properties of the mammary epithelial cell line NMuMG. Clearly visible areas of overgrowth in monolayer cultures of NMuMG were seen in cells infected with the v‐fos‐containing retrovirus but not in cells infected with control virus which did not contain an oncogene. Two cell lines, representing two morphological types of infected cell, were isolated from a morphologically altered region and further characterized. Fos.3.1.NMuMG grew as very spindly cells, achieving a higher density than control cells in 5% foetal calf serum (FCS) but growing very poorly in 1% FCS or in soft agar. Fos.3.3.NMuMG grew to a high density in 5% FCS and to a limited extent in low serum. This cell line also grew in soft agar. Fos.3.3.NMuMG seemed to be more transformed than fos.3.1.NMuMG using the criteria of growth in soft agar and low serum. All the cells used in this study were shown to retain epithelial characteristics by staining for cytokeratins and to contain at least one viral genome by Southern blotting. fos mRNA expression was raised over control levels in the two transformed cell lines.

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One- and two-step transformations of rat thyroid epithelial cells by retroviral oncogenes.

Cited by 229 publications

References 11 publications

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Ras signaling through PI3K confers hormone-independent proliferation that is compatible with differentiation

Signalling of the Ret receptor tyrosine kinase through the c-Jun NH2-terminal protein kinases (JNKs): evidence for a divergence of the ERKs and JNKs pathways induced by Ret

Changes in in vitro growth behaviour of the mammary epithelial cell line NMuMG caused by the v‐fos oncogene

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