title: Excess iodide downregulates Na(+)/I(-) symporter gene transcription through activation of PI3K/Akt pathway.
abstract: Transcriptional mechanisms associated with iodide-induced downregulation of NIS expression remain uncertain. Here, we further analyzed the transcriptional regulation of NIS gene expression by excess iodide using PCCl3 cells. NIS promoter activity was reduced in cells treated for 12-24 h with 10(-5) to 10(-3) M NaI. Site-directed mutagenesis of Pax8 and NF-κB cis-acting elements abrogated the iodide-induced NIS transcription repression. Indeed, excess iodide (10(-3) M) excluded Pax8 from the nucleus, decreased p65 total expression and reduced their transcriptional activity. Importantly, p65-Pax8 physical interaction and binding to NIS upstream enhancer were reduced upon iodide treatment. PI3K/Akt pathway activation by iodide-induced ROS production is involved in the transcriptional repression of NIS expression. In conclusion, the results indicated that excess iodide transcriptionally represses NIS gene expression through the impairment of Pax8 and p65 transcriptional activity. Furthermore, the data presented herein described novel roles for PI3K/Akt signaling pathway and oxidative status in the thyroid autoregulatory phenomenon.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: carolsn.83@gmail.com.
authors.forename: Caroline
authors.initials: C
authors.lastname: Serrano-Nascimento
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: juan_nicola@hotmail.com.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Nicola
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: hyndaia@ig.com.br.
authors.forename: Silvania da Silva
authors.initials: Sda S
authors.lastname: Teixeira
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: lourenco@icb.usp.br.
authors.forename: Leonice Lourenço
authors.initials: LL
authors.lastname: Poyares
authors.affiliation: Department of Biological Sciences, Institute of Environmental, Chemical and Pharmaceutical Sciences, Federal University of São Paulo, Brazil. Electronic address: lellis.unifesp@gmail.com.
authors.forename: Camilo
authors.initials: C
authors.lastname: Lellis-Santos
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: Silvana.bordin@gmail.com.
authors.forename: Silvana
authors.initials: S
authors.lastname: Bordin
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina. Electronic address: amasini@fcq.unc.edu.ar.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Masini-Repiso
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil. Electronic address: mtnunes@icb.usp.br.
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Nunes
mesh_terms: D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D009363:Neoplasm Proteins / Q000378:metabolism; D029543:Nucleocytoplasmic Transport Proteins / Q000378:metabolism; D000072636:PAX8 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D012974:Sodium Iodide / Q000494:pharmacology*; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013972:Thyrotropin / Q000502:physiology; D014158:Transcription, Genetic; D000099209:Sodium-Iodide Symporters
chemical_list: D009363:Neoplasm Proteins; D029543:Nucleocytoplasmic Transport Proteins; D000072636:PAX8 Transcription Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D012974:Sodium Iodide; D027981:Symporters; D013972:Thyrotropin; D000099209:Sodium-Iodide Symporters; C499497:Pax8 protein, rat; C063447:p65 oncofetal mRNA transport protein, rat
keywords: Excess iodide; Na(+/)I(−) symporter (NIS); Nuclear Factor-κB (NF-κB); PI3K/Akt pathway; Paired box 8 (Pax8); Reactive oxygen species (ROS)