RGS 2 expression is regulated by TSH and inhibits TSH receptor signaling

Eszlinger, Markus; Holzapfel, H.; Voigt, Carsten; Arkenau, C; Paschke, Ralf

doi:10.1530/eje.0.1510383

Cited by 21 publications

(14 citation statements)

References 44 publications

(31 reference statements)

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“…A more detailed analysis of the lists of regulated genes (Tables 2-4) confirms previous work on thyroid cells or other cells treated with TSH-or cAMP-enhancing agents for the genes RGS2 (21,22), RGS16 (23), PDE4 (24,25), DIO2 (26)(27)(28), JUNB (19,29), NR4A1 (30), cAMP response element modulator (CREM) (31), TGF␤ (32), IL8 (33), RRAD (34), and EGR1 (19,29).…”

Section: Validation Of Microarray Datasupporting

confidence: 81%

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Staveren¹,

Solís²,

Delys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gs␣ activating mutations have been detected in thyroid autonomous adenomas, Gs␣ mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16 -48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH-cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the oneshot effect of the stimulus. Some were down-or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors.cyclic AMP ͉ microarrays ͉ papillary tumors ͉ thyrotropin T ight regulation of the second messenger cAMP is of crucial importance for cells because it regulates function, differentiation, and proliferation (1). In cells in which cAMP stimulates growth, activating mutations in partners of this pathway induce uncontrolled growth. In most benign thyroid autonomous adenomas, activating mutations have been found in the thyroidstimulating hormone (TSH) receptor (TSHR) (2) and, to a lesser extent, in the Gs␣ protein, an activator of the cAMP-producing adenylyl cyclase (1, 3). These mutations result in a TSHindependent growth and lead to hyperfunction (1). In addition, activating mutations of the Gs␣ protein have been detected in growth hormone-secreting pituitary adenomas (4) and inactivating mutations in the type I-␣ regulatory subunit inhibiting protein kinase A (PKAR1A) in Carney complex, a multiple neoplasia syndrome (5).Our knowledge of the genes regulated by the cAMP-protein kinase A cascade and its uncontrolled activation is still sketchy (6). To gain more insight into the cAMP-activated signal transduction cascade in tumors, human primary cultures of thyrocytes treated for different times with the TSH growth and differentiation stimulus were used as a model. Thyrocytes in primary culture are expected to be better mod...

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Section: Validation Of Microarray Datasupporting

confidence: 81%

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Staveren¹,

Solís²,

Delys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Although a single agonist may upregulate more than one RGS, the GPCR-mediated increase in RGS gene expression is nevertheless selective. For example, the expression of RGS2 but not that of RGS3, 5, 6, 9 10, 12, 14 and 16 was found to be upregulated by the thyroid-stimulating hormone (TSH) in primary thyroid cultures [147]. This suggests that individual RGSs are upregulated to carry out specific functions.…”

Section: Induction Of Rgss By Gpcr Stimulation: Feedback Inhibition Omentioning

confidence: 99%

Regulatory mechanisms involved in modulating RGS function

Jean-Baptiste

Yang

Greenwood

2006

Cell. Mol. Life Sci.

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Regulator of G-Protein Signaling (RGS) refers to a conserved 120-125 amino acid motif that was first identified by its ability to negatively regulate G-Protein-Coupled Receptor (GPCR) signalling. Mechanistically, RGSs were found to regulate GPCR responses by binding to and stimulating the GTPase activity of the receptor-activated GTP-bound G alpha subunits. There are now over 25 mammalian RGSs containing proteins that are reported to carry out a variety of functions, many of which are unrelated to GPCR signalling. RGS proteins range in size from small proteins that contain little more than an RGS box to very large proteins that contain a variety of domains. The selectivity of function of the RGS proteins is attributable to the divergence of the RGS sequences as well as the presence of a variety of functional motifs, which allow them to interact with other proteins. Here we focus on the RGSs that are involved in modulating GPCR signalling by reviewing the diversity of the mechanisms involved in regulating these RGSs.

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“…In the present study, there was no significant correlation between TSHR expression and thyroid hormone levels before initial ATD treatment, but there was an inverse correlation between TSHR expression and thyroid hormone levels after ATD treatment. Eszlinger et al [28] reported that regulators of G-protein signaling 2 (RGS2) inhibit signal transduction by TSHR. It may also have affected TSHR mRNA expression in the present study.…”

Section: Discussionmentioning

confidence: 99%

NIS mRNA Expression Level in Resected Thyroid Tissue as a Marker of Postoperative Hypothyroidism after Subtotal Thyroidectomy in Patients with Graves' Disease

et al. 2008

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Abstract. Subtotal thyroidectomy for Graves' disease sometimes leads to hypothyroidism or relapse during long-term follow-up in a significant proportion of patients. Factors predictive of postoperative hypothyroidism after subtotal thyroidectomy are not known. The objective of this study was to determine the relation between clinical features and expression of transcripts associated with thyroid hormone synthesis in resected thyroid tissues of patients with Graves' disease. Thyroid tissues were obtained from 65 patients with Graves' disease who underwent subtotal thyroidectomy. Expression of mRNAs from thyroglobulin (Tg), TSH receptor (TSHR), thyroid peroxidase (TPO), sodium/iodide symporter (NIS), and the Pendred's syndrome (PDS) genes were analyzed by quantitative reverse transcriptionpolymerase chain reaction. Uni-and multivariate analyses were performed to identify for postoperative hypothyroidism. We detected significant correlations between the NIS mRNA level and levels of free T 3 (fT 3 ) and free T 4 (fT 4 ) and between the Tg mRNA level and goiter weight before initial drug treatment. Mean levels of expression of all five mRNAs were significantly higher in patients who did not require L-thyroxine replacement therapy than in those who required replacement therapy at 6 months after surgery. In patients who did not require replacement therapy, a significant correlation was found between NIS mRNA expression and fT 4 levels. Univariate analysis revealed that decreased NIS mRNA expression (NIS/PGK<1.69) and low TBII levels before initial treatment were significant of postoperative hypothyroidism. Multivariate analysis showed decreased expression of NIS mRNA (NIS/PGK<1.69) to be an independent risk factor for L-thyroxine replacement after surgery (risk ratio, 3.26, confidence interval, 1.36-9.08, p<0.01). NIS expression reflects the level of thyroid hormone synthesis in Graves' disease patients. Evaluation of NIS mRNA expression in thyroid tissues may help determine prognoses of Graves' disease patients, and therefore an appropriate treatment can be determined for each patient.

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RGS 2 expression is regulated by TSH and inhibits TSH receptor signaling

Cited by 21 publications

References 44 publications

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Regulatory mechanisms involved in modulating RGS function

NIS mRNA Expression Level in Resected Thyroid Tissue as a Marker of Postoperative Hypothyroidism after Subtotal Thyroidectomy in Patients with Graves' Disease

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