Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism.

Ledent, Catherine; Dumont, Jacques Emile; Vassart, Gilbert; Parmentier, Marc

doi:10.1002/j.1460-2075.1992.tb05084.x

Cited by 163 publications

(87 citation statements)

References 29 publications

(27 reference statements)

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“…Recent evidence, however, does not support the role of TSH as an initiator of follicular thyroid carcinoma (Ledent et al, 1992;Mazzaferri, 1993;Michiels et al, 1994;Zeiger et al, 1997). The identification of multiple pathways associated with thyroid carcinogenesis suggests that additional genetic changes need to occur for the transformation of the TSH-stimulated hyperproliferative thyroid cells to cancer cells (Ying et al, 2003a;Chevillard et al, 2004).…”

Section: Role Of Pparc In Thyroid Carcinogenesis Y Kato Et Almentioning

confidence: 99%

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

et al. 2005

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The molecular genetic events underlying thyroid carcinogenesis are poorly understood. Mice harboring a knock-in dominantly negative mutant thyroid hormone receptor b (TRb PV/PV mouse) spontaneously develop follicular thyroid carcinoma similar to human thyroid cancer. Using this mutant mouse, we tested the hypothesis that the peroxisome proliferator-activated receptor c (PPARc) could function as a tumor suppressor in thyroid cancer in vivo. Using the offspring from the cross of TRb PV/ þ and PPARc þ /À mice, we found that thyroid carcinogenesis progressed significantly faster in TRb PV/PV mice with PPARc insufficiency from increased cell proliferation and reduced apoptosis. Reduced PPARc protein abundance led to the activation of the nuclear factor-jB signaling pathway, resulting in the activation of cyclin D1 and repression of critical genes involved in apoptosis. Treatment of TRb PV/PV mice with a PPARc agonist, rosiglitazone, delayed the progression of thyroid carcinogenesis by decreasing cell proliferation and activation of apoptosis. These results suggest that PPARc is a critical modifier in thyroid carcinogenesis and could be tested as a therapeutic target in thyroid follicular carcinoma.

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Section: Role Of Pparc In Thyroid Carcinogenesis Y Kato Et Almentioning

confidence: 99%

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

et al. 2005

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“…Transgenic mice featuring the thyroid-specific expression of various oncogenes under the transcriptional control of the bovine thyroglobulin (Tg) promoter recapitulate the thyroid disease spectrum associated with alterations of specific oncogenes in human patients (Ledent et al, 1991(Ledent et al, , 1992. Thyroid targeting of the SV40 LT oncogene, which blocks p53 function, causes very aggressive ATC (Ledent et al, 1991).…”

mentioning

confidence: 99%

Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

et al. 2006

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Ras oncogenes are frequently mutated in thyroid carcinomas. To verify the role played by N-ras in thyroid carcinogenesis, we generated transgenic mice in which a human N-ras(Gln61Lys) oncogene (Tg-N-ras) was expressed in the thyroid follicular cells. Tg-N-ras mice developed thyroid follicular neoplasms; 11% developed follicular adenomas and B40% developed invasive follicular carcinomas, in some cases with a mixed papillary/ follicular morphology. About 25% of the Tg-N-ras carcinomas displayed large, poorly differentiated areas, featuring vascular invasion and forming lung, bone or liver distant metastases. N-ras(Gln61Lys) expression in cultured PC Cl 3 thyrocytes induced thyroid-stimulating hormone-independent proliferation and genomic instability with micronuclei formation and centrosome amplification. These findings support the notion that mutated ras oncogenes could be able to drive the formation of thyroid tumors that can progress to poorly differentiated, metastatic carcinomas.

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“…This oncogenic potential was further illustrated by the occurrence of thyroid adenoma in transgenic mice in which the cAMP pathway was disturbed by the expression of Gsp (Michiels et al, 1994) or of the adenosine A2 receptor (Ledent et al, 1992). We were interested in investigating the possibility that this oncogenic potential could be demonstrable in FRTL-5-derived cells expressing mutant forms of Gsa or TSHR.…”

Section: Oncogenic Transformationmentioning

confidence: 99%

“…In addition, the expression of this protein carrying the A201S mutation in transgenic mice thyrocytes induces hyperfonctioning adenomas after a long latency (8 months) (Michiels et al, 1994). In a parallel model, the expression of the adenosine receptor A2 induces a massive stimulation of the cAMP cascade and leads to hyperplasia and a dramatic hyperthyroidism (Ledent et al, 1992). Considering that both transgenes are expected to stimulate proliferation and di erentiation through the same pathway, this phenotypic di erence is striking.…”

Section: Introductionmentioning

confidence: 99%

Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells

et al. 1998

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An abnormal stimulation of the cAMP pathway has been recognized as the primary event in various pathological situations that lead to goitrogenesis or thyroid tumors. Thyroid adenomas are monoclonal neoplasms that become independent of thyroid stimulating hormone (TSH) in their secretory function and growth. Mutated forms of the TSH receptor (TSHR) and the adenylyl cyclase-activating Gsa protein, which confer a constitutive activity on these proteins, have been observed in human adenomas. The FRTL-5 rat thyroid cell line is a permanent but untransformed line; the growth of which depends on the presence of TSH, and at least in part, on the stimulation of the cAMP pathway. In order to compare the oncogenic potential of the activated mutant Gsa protein and the constitutively activated TSHR, we have transfected FRTL-5 cells with an expression vector bearing either the cDNA of the Gsa gene carrying the A201S mutation or the cDNA of the TSH receptor carrying the M453T mutation recently identi®ed in a case of congenital hyperthyroidism. The expression of these two cDNAs was driven by the bovine thyroglobulin gene promoter. We show that, although the expression of both the Gsa or TSHR mutant proteins leads to TSHindependent proliferation and to constitutive cAMP accumulation in FRTL-5 cells, only the mutant TSHR is able to induce neoplastic transformation, as demonstrated by growth in semi-solid medium and tumorigenesis in nude mice.

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Thyroid expression of an A2 adenosine receptor transgene induces thyroid hyperplasia and hyperthyroidism.

Cited by 163 publications

References 29 publications

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

PPARγ insufficiency promotes follicular thyroid carcinogenesis via activation of the nuclear factor-κB signaling pathway

Thyroid targeting of the N-ras(Gln61Lys) oncogene in transgenic mice results in follicular tumors that progress to poorly differentiated carcinomas

Oncogenic potential of a mutant human thyrotropin receptor expressed in FRTL-5 cells

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