Expression and Regulation of Type II Iodothyronine Deiodinase in Human Thyroid Gland*

Murakami, Masami; Araki, Osamu; Hosoi, Yasuhiro; Kamiya, Yûji; Morimura, Tadashi; Ogiwara, Takayuki; Mizuma, Haruo; Mori, Masataka

doi:10.1210/endo.142.7.8280

Cited by 69 publications

(52 citation statements)

References 13 publications

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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%

“…Genes regulated in a similar direction in cultured thyrocytes and autonomous adenomas, but that are regulated in the inverse way in papillary carcinomas, might reflect the differentiating action of the TSH-cAMP pathway [DIO2 (26,37), HGD (38), FHL1 (39), ITPR1 (39,40), CRABP1 (40,41), and ADM (40)], whereas common expression in the TSH-stimulated thyrocytes, autonomous adenomas, and papillary carcinomas concerns possibly proteins involved in the control or support of cell growth [EFHD2, IER2, KLF6 (10), EGR1 (10), GADD45B, and JUN]. One puzzling common property of autonomous adenomas and papillary carcinomas is the down-regulation of a number of immediate early genes [NR4A1, JUNB (10), KLF10, and ZFP36].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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%

Section: Discussionmentioning

confidence: 99%

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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“…For T 3 , the efficiency of conversion was increased Ϸ2-fold upon TSH or forskolin treatment. The preference in T 3 over T 4 release upon stimulation can easily be explained by the action of type II iodothyronine deiodinase and its well known activation by TSH in the human thyroid (27). Altogether, in vitro stimulation of the TSH͞cAMP cascade reconstituted the key findings of AAs: increased expression of rate-limiting endocytic catalysts leading to accelerated Tg endocytosis and conversion into thyroid hormones.…”

mentioning

confidence: 80%

The endocytic catalysts, Rab5a and Rab7, are tandem regulators of thyroid hormone production

Croizet-Berger

Daumerie

Couvreur

et al. 2002

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

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Rab proteins are small GTPases that control distinct vesicular transport steps. Along the endocytic pathway, Rab5a is a ratelimiting catalyst of internalization, and Rab7 controls trafficking through late endosomes to lysosomes. The dependence of thyroid hormone production by thyrocytes on thyroglobulin endocytosis and intracellular processing in late endosomes͞lysosomes suggests that its rate can be regulated by the expression or function of these endocytic catalysts. We compared the expression level and membrane recruitment of Rab5a and Rab7 in autonomous thyroid adenomas (where the cAMP cascade is constitutively activated) and surrounding quiescent tissues. The concentrations of Rab5a and Rab7, but not of Rab8, were coordinately increased up to 6-fold in adenomas, and correlated with a proportionate decrease in soluble thyroglobulin content (reflecting colloid depletion by accelerated endocytic uptake in hyperactive tissue). In adenomas, a higher proportion of Rab5a and Rab7 was membrane associated, and the equilibrium density of particulate Rab7 and iodine shifted toward lysosomal fractions, indicating that progression along the degradation pathway also was promoted. In cultures of polarized human thyrocytes from normal patients, thyroid-stimulating hormone or forskolin increased, to a similar extent, Rab5a and Rab7 but not Rab8 expression, apical endocytosis of thyroglobulin and lucifer yellow, and basolateral secretion of T 3 and T4. Taken together, these in vivo and in vitro observations demonstrate that thyroid-stimulating hormone, via cAMP, coordinately enhances the expression of Rab5a and Rab7, which promote Tg endocytosis and transfer to lysosomes, respectively, resulting in accelerated thyroid hormone production.

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“…In contrast, type 3 iodothyronine deiodinase (DIO3, D3) catalyzes the inactivation of T 4 and T 3 via inner ring deiodination . Several studies have shown an association between thyroidal status and tumor pathogenesis (Pinto et al 2011, Kim & Cheng 2013 while several reports have documented changes in the expression of deiodinases in benign and malignant tumors (Huang et al 2001, Murakami et al 2001, de Souza Meyer et al 2005, Dentice et al 2007, Meyer et al 2007.…”

Section: Introductionmentioning

confidence: 99%

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

Romitti¹,

Wajner²,

Ceolin³

et al. 2016

Endocrine-Related Cancer

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Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metast atic disease. The objective of this study is to investigate the signaling pathways involved in DIO3 upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples. DIO3 mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein. DIO3 gene silencing was performed via siRNA transfection. DIO3 mRNA levels and activity were readily detected in K1 (BRAF V600E ) and, at lower levels, in TPC-1 (RET/PTC1) cells (P!0.007 and PZ0.02 respectively). Similarly, DIO3 mRNA levels were higher in PTC samples harboring the BRAF V600E mutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (P!0.001). Specific inhibition of BRAF oncogene (PLX4032, 3 mM), MEK (U0126, 10-20 mM) or p38 (SB203580, 10-20 mM) signaling was associated with decreases in DIO3 expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 mM) resulted in markedly decreases in DIO3 mRNA levels. Interestingly, siRNA-mediated DIO3 silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels of DIO3 expression in PTC. Importantly, DIO3 silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.

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Expression and Regulation of Type II Iodothyronine Deiodinase in Human Thyroid Gland*

Cited by 69 publications

References 13 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

The endocytic catalysts, Rab5a and Rab7, are tandem regulators of thyroid hormone production

MAPK and SHH pathways modulate type 3 deiodinase expression in papillary thyroid carcinoma

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