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rdf:type |
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lifeskim:mentions |
umls-concept:C0032005,
umls-concept:C0035335,
umls-concept:C0040135,
umls-concept:C0174680,
umls-concept:C0205263,
umls-concept:C0243045,
umls-concept:C0330390,
umls-concept:C0597357,
umls-concept:C1326912,
umls-concept:C1515877,
umls-concept:C1704259,
umls-concept:C1705987,
umls-concept:C1879547
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pubmed:issue |
1
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pubmed:dateCreated |
2004-12-16
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pubmed:abstractText |
Thyroid-stimulating hormone (TSH)-secreting tumors (TSH-omas) are pituitary tumors that constitutively secrete TSH. The molecular genetics underlying this abnormality are not known. We discovered that a knock-in mouse harboring a mutated thyroid hormone receptor (TR) beta (PV; TRbeta(PV/PV) mouse) spontaneously developed TSH-omas. TRbeta(PV/PV) mice lost the negative feedback regulation with highly elevated TSH levels associated with increased thyroid hormone levels (3,3',5-triiodo-l-thyronine [T3]). Remarkably, we found that mice deficient in all TRs (TRalpha1(-/-) TRbeta(-/-)) had similarly increased T3 and TSH levels, but no discernible TSH-omas, indicating that the dysregulation of the pituitary-thyroid axis alone is not sufficient to induce TSH-omas. Comparison of gene expression profiles by cDNA microarrays identified overexpression of cyclin D1 mRNA in TRbeta(PV/PV) but not in TRalpha1(-/-) TRbeta(-/-) mice. Overexpression of cyclin D1 protein led to activation of the cyclin D1/cyclin-dependent kinase/retinoblastoma protein/E2F pathway only in TRbeta(PV/PV) mice. The liganded TRbeta repressed cyclin D1 expression via tethering to the cyclin D1 promoter through binding to the cyclic AMP response element-binding protein. That repression effect was lost in mutant PV, thereby resulting in constitutive activation of cyclin D1 in TRbeta(PV/PV) mice. The present study revealed a novel molecular mechanism by which an unliganded TRbeta mutant acts to contribute to pituitary tumorigenesis in vivo and provided mechanistic insights into the understanding of pathogenesis of TSH-omas in patients.
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-10022404,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-10201372,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-10346821,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-10428804,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-10723566,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11069286,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11327621,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11385503,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11518802,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11701737,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11704997,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11734632,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-11909518,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-12805224,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-14519205,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-15059606,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-15062569,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-1704102,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-3006034,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-4524638,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-7565785,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-7566114,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-7838159,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-8633054,
http://linkedlifedata.com/resource/pubmed/commentcorrection/15601836-8969971
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Cell Cycle Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclic AMP,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin D1,
http://linkedlifedata.com/resource/pubmed/chemical/Cyclin-Dependent Kinases,
http://linkedlifedata.com/resource/pubmed/chemical/DNA, Complementary,
http://linkedlifedata.com/resource/pubmed/chemical/DNA-Binding Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/E2F Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Glutathione Transferase,
http://linkedlifedata.com/resource/pubmed/chemical/Ligands,
http://linkedlifedata.com/resource/pubmed/chemical/Pituitary Hormones,
http://linkedlifedata.com/resource/pubmed/chemical/RNA,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Messenger,
http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Thyroid Hormone,
http://linkedlifedata.com/resource/pubmed/chemical/Retinoblastoma Protein,
http://linkedlifedata.com/resource/pubmed/chemical/Thyroid Hormone Receptors beta,
http://linkedlifedata.com/resource/pubmed/chemical/Transcription Factors,
http://linkedlifedata.com/resource/pubmed/chemical/Triiodothyronine
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pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
0270-7306
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pubmed:author |
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pubmed:issnType |
Print
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pubmed:volume |
25
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
124-35
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pubmed:dateRevised |
2009-11-19
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pubmed:meshHeading |
pubmed-meshheading:15601836-Animals,
pubmed-meshheading:15601836-Mice,
pubmed-meshheading:15601836-Pituitary Hormones,
pubmed-meshheading:15601836-Pituitary Gland,
pubmed-meshheading:15601836-Mutation,
pubmed-meshheading:15601836-Pituitary Neoplasms,
pubmed-meshheading:15601836-RNA,
pubmed-meshheading:15601836-Triiodothyronine,
pubmed-meshheading:15601836-Time Factors,
pubmed-meshheading:15601836-RNA, Messenger,
pubmed-meshheading:15601836-Protein Binding,
pubmed-meshheading:15601836-Organ Size,
pubmed-meshheading:15601836-Cyclic AMP,
pubmed-meshheading:15601836-Mice, Inbred C57BL,
pubmed-meshheading:15601836-Nucleic Acid Hybridization,
pubmed-meshheading:15601836-Cell Proliferation,
pubmed-meshheading:15601836-Ligands,
pubmed-meshheading:15601836-Plasmids,
pubmed-meshheading:15601836-Gene Expression Regulation,
pubmed-meshheading:15601836-Promoter Regions, Genetic,
pubmed-meshheading:15601836-DNA-Binding Proteins
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