Thyroid-specific gene expression

Damante, Giuseppe; Lauro, Roberto Di

doi:10.1016/0167-4781(94)90176-7

Cited by 207 publications

(124 citation statements)

References 94 publications

Supporting

Mentioning

117

Contrasting

Unclassified

Order By: Relevance

“…Thyroid follicular cells are highly specialized epithelial cells which are devoted to synthesis, storage and release of thyroid hormones. This process requires the expression of a set of cell-type-speci®c gene products, which include thyroglobulin (TG), thyroperoxidase (TPO), thyroidstimulating hormone receptor (TSH-R) and Na + /l 7 symporter (NIS) (Damante and Di Lauro, 1994). Studies on the TG and TPO promoters have allowed the identi®cation of three thyroid-speci®c transcription factors, TTF-1 (Thyroid Transcription Factor-1), TTF-2 (Thyroid Transcription Factor-2) and Pax-8 (belonging to the family of the paired domain proteins), involved in the onset and maintenance of the di erentiation status (Guazzi et al, 1990;Zannini et al, 1992Zannini et al, , 1997.…”

Section: Introductionmentioning

confidence: 99%

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

1998

View full text Add to dashboard Cite

Activating point mutations in the Ras oncogene occur in a large number of human tumors, especially of epithelial origin. In thyroid follicular cells, ectopic expression of oncogenic H-Ras results in growth factor-independent proliferation, loss of di erentiation and tumor formation in nude mice. In ®broblasts concomitant activation of the MAP kinase cascade and the small GTPase Rac-1 leads to full malignant transformation. We have tested the e ects of these key downstream mediators of Ras in thyroid epithelial cells, by stably expressing either a constitutively active form of MEK-1 (MEK DN3/S218E/S222D ), a constitutively active form of Rac-1 (Val12-Rac), or both. While the activation of one molecule or the other results in a weak phenotype, concomitant activation of both MEK-1 and Rac-1 in thyroid cells leads to growth factor-independent proliferation, morphological transformation and anchorage-independent growth. However, in contrast to Ras-transformed thyroid cells, the ones expressing the constitutively active forms of MEK-1 and Rac-1 maintain their di erentiate phenotype and fail to form tumors when injected into nude mice. Thus, in thyroid epithelial cells, concomitant activation of MEK-1 and Rac-1 can reproduce only a subset of the Rasinduced e ects and is not su cient to cause full malignant transformation. Signi®cantly, Ras-mediated increased proliferation and loss of di erentiation can be dissociated in these cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

1998

View full text Add to dashboard Cite

show abstract

“…Four genes encoding thyroid-specific proteins have been cloned: thyroglobulin (Tg), thyroperoxidase (TPO), thyroid-stimulating hormone receptor (1), and, more recently, thyroid iodine transporter (2). This tissue-restricted protein production is regulated, at least in part, by the thyroid-specific nuclear factors, thyroid transcription factors 1 and 2 (TTF-1 and TTF-2) (3, 4) and Pax-8 (5).…”

mentioning

confidence: 99%

Thyroid Transcription Factor-1 in Normal, Hyperplastic, and Neoplastic Follicular Thyroid Cells Examined by Immunohistochemistry and Nonradioactive In Situ Hybridization

et al. 2000

View full text Add to dashboard Cite

Thyroid transcription factor-1 (TTF-1) has been known to regulate the transcriptional activity of thyroid-specific genes. We examined the expression of TTF-1 in non-neoplastic and neoplastic thyroid tissues. By immunohistochemistry, the nuclei of normal and hyperplastic follicular cells strongly reacted with the antibody against TTF-1. Immunohistochemistry also revealed a distinctive nuclear positivity of TTF-1 in all 33 differentiated follicular cell tumors, including 15 follicular adenomas, 5 follicular carcinomas, and 13 papillary carcinomas. No immunoreactions were observed in three of four undifferentiated carcinomas, whereas an isolated and weak nuclear positivity was obtained in one. In normal and hyperplastic tissues, the distribution of TTF-1 was fairly related to that of thyroid-specific proteins thyroglobulin and thyroperoxidase. However, discrepancies in the distribution were observed in tumor tissues. By in situ hybridization, the riboprobe hybridized distinctively with the cytoplasm of neoplastic cells as well as normal follicular cells. Papillary carcinoma cells expressed TTF-1 mRNA in all but two cases, and its expression was also demonstrated in one of four undifferentiated carcinomas. Reverse transcription-polymerase chain reaction confirmed the presence of TTF-1 mRNA in two human undifferentiated carcinoma cell lines, TTA-1 and TTA-2. In conclusion, the investigation of TTF-1 provides useful information on the functional activities and/or differentiation of thyroid tumors and may lead to an increase in our understanding of the biologic nature of thyroid tumors.

show abstract

“…These cells are responsible for thyroid hormone synthesis and are characterized by the expression of thyroid-specific genes such as thyroglobulin (Tg) and thyroperoxidase (TPO), which are exclusively expressed in this organ, and by the expression of genes that have been detected only in a few tissues other than the thyroid, such as the TSH receptor (TSHr) and the sodium͞iodide symporter (NIS) (2,3). Tg and TPO promoters have been extensively studied, and three transcription factors have been cloned that specifically bind and activate these two promoters (3). The three factors are TTF-1 (Thyroid Transcription Factor-1), TTF-2 (Thyroid Transcription Factor-2), and Pax8.…”

mentioning

confidence: 99%

Pax8 has a key role in thyroid cell differentiation

Magliano

Lauro

Zannini

2000

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

Self Cite

219

140

View full text Add to dashboard Cite

Transformation of rat thyroid cells with polyoma virus middle T antigen results in loss of the thyroid-differentiated phenotype, measured as the expression of the thyroglobulin (Tg), thyroperoxidase (TPO), and sodium͞iodide symporter (NIS) genes. Among the transcription factors involved in the regulation of these genes, TTF-1 and TTF-2 were still detected at nearly wild-type levels, while a specific loss of the paired domain transcription factor Pax8 was observed. In this study, we used the PCPy cell line as a model system to study the role of Pax8 in thyroid differentiation. We demonstrate that the reintroduction of Pax8 in PCPy cells is sufficient to activate expression of the endogenous genes encoding thyroglobulin, thyroperoxidase, and sodium͞iodide symporter. Thus, this cell system provides direct evidence for the ability of Pax8 to activate transcription of thyroid-specific genes at their chromosomal locus and strongly suggests a fundamental role of this transcription factor in the maintenance of functional differentiation in thyroid cells. Moreover, we show that Pax8 and TTF-1 cooperate in the activation of the thyroglobulin promoter and that additional thyroid-specific mechanism(s) are involved in such a cooperation. To identify the Pax8 domain able to mediate the specific activation of the thyroglobulin promoter, we transfected in PCPy cells three different Pax8 isoforms. The results of such experiments indicate that for the transcriptional activation of thyroid-specific genes, Pax8 uses an as yet unidentified functional domain.Pax genes ͉ gene expression T erminally differentiated cells express genes whose products are undetectable in other cell types. The isolation of regulatory DNA sequences responsible for such cell-type-specific expression and the cloning of the cDNAs encoding cognate transcription factors revealed, in the majority of cases, that a combination of transcription factors is unique to a cell type. Thus, transcription of cell-type-specific genes appears to depend on synergy between transcription factors (1, 2). Frequently, transcription factors controlling the expression of genes specific to the terminal differentiation state of a given cell type play an additional role earlier in the development of the same cell type. As a consequence, the identification of factors controlling cell-type-specific gene expression also provides relevant information on earlier developmental stages in many organs and cell lineages. However, a direct assessment of the role of many transcription factors in cell-type-specific gene expression has proven difficult, given that mice lacking the relevant transcription factors often show complete absence of the implicated cell type.To elucidate the mechanism(s) operating in the establishment and maintenance of cell-type-specific expression, we have been studying a model system represented by the thyroid follicular cells, the most abundant cell population of the thyroid gland. These cells are responsible for thyroid hormone synthesis and are characterized by the expr...

show abstract

Thyroid-specific gene expression

Cited by 207 publications

References 94 publications

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

Concomitant activation of MEK-1 and Rac-1 increases the proliferative potential of thyroid epithelial cells, without affecting their differentiation

Thyroid Transcription Factor-1 in Normal, Hyperplastic, and Neoplastic Follicular Thyroid Cells Examined by Immunohistochemistry and Nonradioactive In Situ Hybridization

Pax8 has a key role in thyroid cell differentiation

Contact Info

Product

Resources

About