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1.
Life Sci ; 82(13-14): 677-83, 2008 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-18304585

RESUMO

Although severe deficiency of bioactive vitamin D (1,25OH2D) causes rickets, mild insufficiency of the hormone, known as hypovitaminosis D, is responsible for the occurrence of secondary hyperparathyroidism and osteoporosis. To clarify the pathophysiology of the disease, we studied the negative feedback effect of 1,25OH2D and its precursor 25OHD on the transcriptional activity of parathyroid hormone (PTH) gene using the PT-r parathyroid cell line. We found that PT-r cells express endogenous 1alpha-hydroxylase as well as PTH mRNAs. We also found the potent suppressive effect of physiological concentration of 25OHD on the transcriptional activity of PTH gene. A similar effect was obtained with 1,25OH2D but only with pharmacological concentration. Interestingly, the effect of 25OHD was completely abolished when the cells were treated with 1alpha-hydroxylase inhibitor ketoconazole. These results suggest that the negative feedback regulation of vitamin D on PTH gene transcription occurs not by the end-product 1,25OH2D but by its prohormone 25OHD via intracellular activation by 1alpha-hydroxylase within the parathyroid cells.


Assuntos
Hormônio Paratireóideo/genética , Transcrição Gênica , Deficiência de Vitamina D/genética , Vitamina D/análogos & derivados , Animais , Sequência de Bases , Linhagem Celular , Clonagem Molecular , Inibidores Enzimáticos/farmacologia , Retroalimentação Fisiológica , Vetores Genéticos , Humanos , Hiperparatireoidismo Secundário/genética , Cetoconazol/farmacologia , Luciferases/genética , Dados de Sequência Molecular , Glândulas Paratireoides/citologia , Glândulas Paratireoides/enzimologia , Glândulas Paratireoides/metabolismo , Plasmídeos , Regiões Promotoras Genéticas , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Esteroide Hidroxilases/antagonistas & inibidores , Esteroide Hidroxilases/fisiologia , Transcrição Gênica/efeitos dos fármacos , Vitamina D/farmacologia , Vitamina D/fisiologia
2.
Bone ; 47(3): 534-41, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20558332

RESUMO

Expression of the PTH gene is known to be under strict tissue-specific control and is also regulated by extracellular calcium and 1,25(OH)(2)D. However, the precise mode of transcriptional regulation remains to be elucidated, because of the unavailability of appropriate cell lines derived from the parathyroid gland. We tried to identify the transcription factor(s) regulating the human PTH gene transcription using the PT-r cell line. We found that PT-r cells endogenously express PTH and several parathyroid-related genes. Using the cells, we investigated the transcriptional regulation of human PTH gene. We found that GCMB binds to the PTH gene 5'-promoter (-390/-383 bp) and positively regulates its transcription. On the other hand, 1,25(OH)(2)D(3), and, in the presence of the calcium sensing receptor, high extracellular calcium, exerted inhibitory effects on PTH gene expression. These results indicate that GCMB and vitamin D receptor are involved in the positive and negative regulation of PTH gene expression, respectively. Our data also suggest that PT-r cells retain some of the characteristics of parathyroid cells.


Assuntos
Calcitriol/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Proteínas Nucleares/metabolismo , Glândulas Paratireoides/citologia , Hormônio Paratireóideo/genética , Fatores de Transcrição/metabolismo , Transcrição Gênica , Sequência de Bases , Conservadores da Densidade Óssea/metabolismo , Linhagem Celular , Humanos , Dados de Sequência Molecular , Proteínas Nucleares/genética , Hormônio Paratireóideo/metabolismo , Regiões Promotoras Genéticas , Receptores de Calcitriol/genética , Receptores de Calcitriol/metabolismo , Fatores de Transcrição/genética
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