Document Detail

NF-kappaB p65 subunit mediates lipopolysaccharide-induced Na(+)/I(-) symporter gene expression by involving functional interaction with the paired domain transcription factor Pax8.
MedLine Citation:
PMID:  20667985     Owner:  NLM     Status:  MEDLINE    
The Gram-negative bacterial endotoxin lipopolysaccharide (LPS) elicits a variety of biological responses. Na(+)/I(-) symporter (NIS)-mediated iodide uptake is the main rate-limiting step in thyroid hormonogenesis. We have recently reported that LPS stimulates TSH-induced iodide uptake. Here, we further analyzed the molecular mechanism involved in the LPS-induced NIS expression in Fisher rat thyroid cell line 5 (FRTL-5) thyroid cells. We observed an increase in TSH-induced NIS mRNA expression in a dose-dependent manner upon LPS treatment. LPS enhanced the TSH-stimulated NIS promoter activity denoting the NIS-upstream enhancer region (NUE) as responsible for the stimulatory effects. We characterized a novel putative conserved kappaB site for the transcription factor nuclear factor-kappaB (NF-kappaB) within the NUE region. NUE contains two binding sites for the transcription factor paired box 8 (Pax8), main regulator of NIS transcription. A physical interaction was observed between the NF-kappaB p65 subunit and paired box 8 (Pax8), which appears to be responsible for the synergic effect displayed by these transcription factors on NIS gene transcription. Moreover, functional blockage of NF-kappaB signaling and site-directed mutagenesis of the kappaB cis-acting element abrogated LPS stimulation. Silencing expression of p65 confirmed its participation as an effector of LPS-induced NIS stimulation. Furthermore, chromatin immunoprecipitation corroborated that NIS is a novel target gene for p65 transactivation in response to LPS. Moreover, we were able to corroborate the LPS-stimulatory effect on thyroid cells in vivo in LPS-treated rats, supporting that thyrocytes are capable of responding to systemic infections. In conclusion, our results reveal a new mechanism involving p65 in the LPS-induced NIS expression, denoting a novel aspect in thyroid cell differentiation.
Juan Pablo Nicola; Magalí Nazar; Iván Darío Mascanfroni; Claudia Gabriela Pellizas; Ana María Masini-Repiso
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-07-28
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  24     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-30     Completed Date:  2010-12-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1846-62     Citation Subset:  IM    
Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas (CIBICI-CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000 Córdoba, Argentina.
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MeSH Terms
Base Sequence
Binding Sites
Enhancer Elements, Genetic / genetics
Gene Expression Regulation / drug effects*
Gene Silencing / drug effects
Lipopolysaccharides / pharmacology*
Molecular Sequence Data
Paired Box Transcription Factors / metabolism*
Protein Binding / drug effects
RNA, Messenger / genetics,  metabolism
RNA, Small Interfering / metabolism
Symporters / genetics*,  metabolism
Thyroid Gland / cytology,  drug effects,  metabolism
Thyrotropin / pharmacology
Transcription Factor RelA / metabolism*
Transcription, Genetic / drug effects
Transcriptional Activation / drug effects
Up-Regulation / drug effects
Reg. No./Substance:
0/Lipopolysaccharides; 0/PAX8 protein, human; 0/Paired Box Transcription Factors; 0/RNA, Messenger; 0/RNA, Small Interfering; 0/Symporters; 0/Transcription Factor RelA; 0/sodium-iodide symporter; 9002-71-5/Thyrotropin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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