TSH and cAMP Do Not Signal Mitogenesis through Ras Activation

Keymeulen, Alexandra Van; Roger, Pierre P.; Dumont, Jacques Emile; Dremier, Sarah

doi:10.1006/bbrc.2000.2900

Cited by 25 publications

(25 citation statements)

References 42 publications

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“…In dog and human thyrocytes in primary cultures, after delayed induction of insulin receptors by TSH, physiological concentrations of insulin also permit the proliferative action of TSH (Burikhanov et al, 1996;Van Keymeulen et al, 2000a). In dog thyrocytes, in the absence of insulin/IGF-I, acetylcholine ) and phorbol myristate ester are also permissive for TSH-cAMP mitogenic stimulation action, presumably by the stimulation of protein kinase C and consequently activation of Ras (Van Keymeulen et al, 2000b), MAP kinase and increased cyclin D expression . Thus the IGF-I-PI-3K pathway may complement the TSH-cAMP and the EGF-MAPK cascades by at least partially different mechanisms.…”

Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

“…It totally diverges from the phosphorylations induced by EGF and phorbol esters (TPA) (Contor et al, 1988). EGF, HGF and phorbol ester actions rapidly converge on the activation of Ras (Van Keymeulen et al, 2000b) and the resulting activation of ERK1/2 and p90 RSK (Coulonval et al, 2000;Lamy et al, 1993;Vandeput et al, 2003). PI-3-kinase and its effector enzyme PKB are activated for several hours only by insulin and IGF-I, the effect of EGF being weak and short lived (Coulonval et al, 2000).…”

Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

“…2). By contrast, TSH and cAMP are very unique as mitogens, as they do not activate Ras, the PI-3K-PKB pathway, or any of different classes of MAP kinases in dog thyrocytes (Coulonval et al, 2000;Lamy et al, 1993;Vandeput et al, 2003;Van Keymeulen et al, 2000b) (Fig.2). TSH and cAMP also do not activate MAP kinases in human thyrocytes (Vandeput et al, 2003).…”

Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

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Signal transduction in the human thyrocyte and its perversion in thyroid tumors

Roger

Staveren

Coulonval

et al. 2010

Molecular and Cellular Endocrinology

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The study of normal signal transduction pathways regulating the proliferation and differentiation of a cell type allows to predict and to understand the perversions of these pathways which lead to tumorigenesis. In the case of the human thyroid cell, three cascades are mostly involved in tumorigenesis:the TSH receptor-cyclic AMP cascade, the constitutive activation of which leads to autonomous adenomas and congenital hyperthyroidism.the growth factor-Ras-MAP kinase pathway, whose constitutive activation causes follicular and papillary carcinomas.the PI-3Kinase-PKB pathway, the activity of which is necessary for both pathways and the corresponding tumors.The pathways and genetic events affecting them are described. Caveats in the use of models and the interpretation of results are formulated and the still pending questions are outlined.

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Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

Section: Our Present Knowledge Of Signal Transduction Pathways Comentioning

confidence: 99%

See 1 more Smart Citation

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

Roger

Staveren

Coulonval

et al. 2010

Molecular and Cellular Endocrinology

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“…Although the activation of PKA was necessary for cell cycle progression, it has been suggested that PKA-independent mechanisms might be required in cAMP-mediated growth of thyroid cells (8,9). Ras activity was required for DNA synthesis in TSH-stimulated WRT cells (10), but TSH did not activate directly the p42/p44 mitogen-activated protein kinase pathway in FRTL-5 cells and in dog thyrocytes (11,12). In addition, TSH or cAMP did not activate directly the phosphatidyl inositol-3 kinase (PI3K)/Akt pathway in dog thyrocytes (13) or FRTL-5 cells (14), but stimulated the formation of the PI3K -Ras complex in the latter cell type (15).…”

Section: Introductionmentioning

confidence: 99%

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

Correze¹,

Blondeau²,

Pomérance³

2005

eur j endocrinol

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Objective: Thyrotropin activates the cAMP pathway in thyroid cells, and stimulates cell cycle progression in cooperation with insulin or insulin-like growth factor-I. Because p38 mitogen-activated protein kinases (p38 MAPKs) were stimulated by cAMP in the FRTL-5 rat thyroid cell line, we investigated (i) the effect of the specific inhibition of p38 MAPKs on FRTL-5 cell proliferation and (ii) the mechanism of action of p38 MAPKs on cell cycle control, by studying the expression and/or the activity of several cell cycle regulatory proteins in FRTL-5 cells. Methods: DNA synthesis was monitored by incorporation of [ 3 H]thymidine into DNA and the cell cycle distribution was assessed by fluorescence-activated cell sorter analysis. Expression of cell cycle regulatory proteins was determined by Western blot analysis. Cyclin-dependent kinase 2 (Cdk2) activity associated to cyclin E was immunoprecipitated and was measured by an in vitro kinase assay. Results: SB203580, an inhibitor of a and b isoforms of p38 MAPKs, but not its inactive analog SB202474, inhibited DNA synthesis and the G1-S transition induced by forskolin plus insulin. SB203580 inhibited specifically p38 MAPK activity but not other kinase activities such as Akt and p70-S6 kinase. Treatment of FRTL-5 cells with SB203580 decreased total and cyclin E-associated Cdk2 kinase activity stimulated with forskolin and insulin. However, inhibition of p38 MAPKs by SB203580 was without effect on total cyclin E and Cdk2 levels. The decrease in Cdk2 kinase activity caused by SB203580 treatment was not due to an increased expression of p21Cip1 or p27 Kip1 inhibitory proteins. In addition, SB203580 affected neither Cdc25A phosphatase expression nor Cdk2 Tyr-15 phosphorylation. Inhibition of p38 MAPKs decreased Cdk2-cyclin E activation by regulating the subcellular localization of Cdk2 and its phosphorylation on Thr-160. Conclusions: These results indicate that p38 MAPK activity is involved in the regulation of cell cycle progression in FRTL-5 thyroid cells, at least in part by increasing nuclear Cdk2 activity. 153 123-133 European Journal of Endocrinology

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“…Besides the previously mentioned proteins other related hormones, such as hCG, or antibodies from autoinmune diseases, such as Graves' disease, may also interact with the TSHR and be involved in thyroid cancers. Anti-TSHR antibodies binding to the TSHR in thyroid nodules might promote growth via direct and indirect mechanisms such as upregulating the expression of insulin receptors (156), which may transduce IGF-II growth effects (157). Anti-TSHR antibodies also stimulate angiogenesis upregulating VEGF and its receptor (flt) in thyroid cells (158).…”

Section: Postranslational Modifications and Protein Interactionsmentioning

confidence: 99%

TSH signalling and cancer

García-Jiménez

Santisteban

2007

Arq Bras Endocrinol Metab

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Thyroid cancers are the most frequent endocrine neoplasms and mutations in the thyrotropin receptor (TSHR) are unusually frequent. Here we present the state-of-the-art concerning the role of TSHR in thyroid cancer and discuss it in light of the cancer stem cell theory or the classical view. We briefly review the gene and protein structure updating the cancer related TSHR mutations database. Intriguingly, hyperfunctioning TSHR mutants characterise differentiated cancers in contrast to undifferentiated thyroid cancers which very often bear silenced TSHR. It remains unclear whether TSHR alterations in thyroid cancers play a role in the onset or they appear as a consequence of genetic instability during evolution, but the presence of functional TSHR is exploited in therapy. We outline the signalling network build up in the thyrocyte between TSHR/PKA and other proliferative pathways such as Wnt, PI3K and MAPK. This network's integrity surely plays a role in the onset/evolution of thyroid cancer and needs further research. Lastly, future investigation of epigenetic events occurring at the TSHR and other loci may give better clues for molecular based therapy of undifferentiated thyroid carcinomas. Targeted demethylating agents, histone deacetylase inhibitors combined with retinoids and specific RNAis may help treatment in the future. RESUMOSinalização de TSH e Câncer. Os cânceres de tiróide são as neoplasias endócrinas mais frequentes e as mutações no receptor de tirotrofina (TSHR) são incomumente frequentes. Nesta revisão nós apresentamos o "estado da arte" com relação ao papel do TSHR no câncer de tiróide e o discutimos à luz da teoria da célula matriz do câncer ou a visão clássica. Revisamos brevemente a estrutura do gene e da proteína, atualizando a base de dados das mutações do TSHR relacionadas ao câncer. Curiosamente, mutações do TSHR com hiperfunção caracterizam cânceres diferenciados, em contraste com os cânceres de tiróide indiferenciados, os quais muito comumente mostram TSHR silenciados. Permanece obscuro se as alterações do TSHR em cânceres de tiróide têm algum papel no surgimento ou se elas aparecem como conseqüência da instabilidade genética durante seu desenvolvimento, mas a presença de TSHR funcional é explorada na terapia. Nós delineamos a rede de sinalizacão desenvolvida no tirócito entre TSHR/PKA e outras vias proliferativas como a Wnt, PI3k e MAPK. A integridade desta rede certamente tem um papel no surgimento/evolução do câncer de tiróide e necessita de novas pesquisas. Finalmente, novas investigacões sobre os eventos epigenéticos que ocorrem no TSHR e outros locais poderão trazer novas informações para uma terapia de base molecular nos carcinomas indiferenciados de tiróide. Agentes demetilantes direcionados, inibidores da histona-deacetilase, combinados com retinóides e RNAs específicos poderão auxiliar no tratamento futuro.

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TSH and cAMP Do Not Signal Mitogenesis through Ras Activation

Cited by 25 publications

References 42 publications

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

Signal transduction in the human thyrocyte and its perversion in thyroid tumors

p38 mitogen-activated protein kinase contributes to cell cycle regulation by cAMP in FRTL-5 thyroid cells

TSH signalling and cancer

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