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Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression.

Upregulation of ADAM-12, a novel member of the multifunctional ADAM family of proteins is linked to cancer, arthritis and cardiac hypertrophy. Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placen... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America January 4, 2011, Vol.108(1), pp.103-108
Main Author: Ray, Bimal K
Other Authors: Dhar, Srijita , Shakya, Arvind , Ray, Alpana
Format: Electronic Article Electronic Article
Language: English
Subjects:
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1008831108
Link: http://search.proquest.com/docview/822710373/?pq-origsite=primo
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title: Z-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression.
format: Article
creator:
  • Ray, Bimal K
  • Dhar, Srijita
  • Shakya, Arvind
  • Ray, Alpana
subjects:
  • Adam Proteins–Metabolism
  • Adam12 Protein–Genetics
  • Amino Acid Sequence–Genetics
  • Base Sequence–Metabolism
  • Blotting, Northern–Metabolism
  • Cell Line–Genetics
  • Chromatin Immunoprecipitation–Genetics
  • DNA Primers–Genetics
  • DNA, Z-Form–Physiology
  • DNA-Binding Proteins–Metabolism
  • Dinucleotide Repeats–Genetics
  • Electrophoretic Mobility Shift Assay–Genetics
  • Exons–Genetics
  • Gene Expression Regulation–Genetics
  • Humans–Genetics
  • Membrane Proteins–Genetics
  • Molecular Sequence Data–Genetics
  • Sequence Alignment–Genetics
  • Sequence Analysis, DNA–Genetics
  • Silencer Elements, Transcriptional–Genetics
  • DNA Primers
  • DNA, Z-Form
  • DNA-Binding Proteins
  • Membrane Proteins
  • Adam Proteins
  • Adam12 Protein
  • Adam12 Protein, Human
ispartof: Proceedings of the National Academy of Sciences of the United States of America, January 4, 2011, Vol.108(1), pp.103-108
description: Upregulation of ADAM-12, a novel member of the multifunctional ADAM family of proteins is linked to cancer, arthritis and cardiac hypertrophy. Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placenta, during development in neonatal skeletal muscle and bone and in regenerating muscle. Studies on ADAM-12 regulation have identified a highly conserved negative regulatory element (NRE) at the 5'-UTR of human ADAM12 gene, which acts as a transcriptional repressor. The NRE contains a stretch of dinucleotide-repeat sequence that is able to adopt a Z-DNA conformation both in vitro and in vivo and interacts with hZ[[alpha].sub.ADAR1], a bona fide Z-DNA-binding protein. Substitution of the dinucleotide-repeat-element with a non-Z-DNA-forming sequence inhibited NRE function. We have detected a NRE DNA-binding protein activity in several tissues where ADAM-12 expression is low while no such activity was seen in the placenta where ADAM-12 expression is high. These observations suggest that interaction of these proteins with ADAM-12 NRE is critical for transcriptional repression of ADAM-12. We also show that the Z-DNA forming transcriptional repressor element, by interacting with these putative Z-DNA-binding proteins, is involved in the maintenance of constitutive low-level expression of human ADAM-12. Together these results provide a foundation for therapeutic down-regulation of ADAM-12 in cancer, arthritis and cardiac hypertrophy. gene regulation | repressor proteins | pathogenesis doi/ 10.1073/pnas.1008831108
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1008831108
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleZ-DNA-forming silencer in the first exon regulates human ADAM-12 gene expression.
creatorRay, Bimal K ; Dhar, Srijita ; Shakya, Arvind ; Ray, Alpana
contributorRay, Bimal K (correspondence author) ; Ray, Bimal K (record owner)
ispartofProceedings of the National Academy of Sciences of the United States of America, January 4, 2011, Vol.108(1), pp.103-108
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1008831108
subjectAdam Proteins–Metabolism ; Adam12 Protein–Genetics ; Amino Acid Sequence–Genetics ; Base Sequence–Metabolism ; Blotting, Northern–Metabolism ; Cell Line–Genetics ; Chromatin Immunoprecipitation–Genetics ; DNA Primers–Genetics ; DNA, Z-Form–Physiology ; DNA-Binding Proteins–Metabolism ; Dinucleotide Repeats–Genetics ; Electrophoretic Mobility Shift Assay–Genetics ; Exons–Genetics ; Gene Expression Regulation–Genetics ; Humans–Genetics ; Membrane Proteins–Genetics ; Molecular Sequence Data–Genetics ; Sequence Alignment–Genetics ; Sequence Analysis, DNA–Genetics ; Silencer Elements, Transcriptional–Genetics ; DNA Primers ; DNA, Z-Form ; DNA-Binding Proteins ; Membrane Proteins ; Adam Proteins ; Adam12 Protein ; Adam12 Protein, Human
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descriptionUpregulation of ADAM-12, a novel member of the multifunctional ADAM family of proteins is linked to cancer, arthritis and cardiac hypertrophy. Basal expression of ADAM-12 is very low in adult tissues but rises markedly in response to certain physiological cues, such as during pregnancy in the placenta, during development in neonatal skeletal muscle and bone and in regenerating muscle. Studies on ADAM-12 regulation have identified a highly conserved negative regulatory element (NRE) at the 5'-UTR of human ADAM12 gene, which acts as a transcriptional repressor. The NRE contains a stretch of dinucleotide-repeat sequence that is able to adopt a Z-DNA conformation both in vitro and in vivo and interacts with hZ[[alpha].sub.ADAR1], a bona fide Z-DNA-binding protein. Substitution of the dinucleotide-repeat-element with a non-Z-DNA-forming sequence inhibited NRE function. We have detected a NRE DNA-binding protein activity in several tissues where ADAM-12 expression is low while no such activity was seen in the placenta where ADAM-12 expression is high. These observations suggest that interaction of these proteins with ADAM-12 NRE is critical for transcriptional repression of ADAM-12. We also show that the Z-DNA forming transcriptional repressor element, by interacting with these putative Z-DNA-binding proteins, is involved in the maintenance of constitutive low-level expression of human ADAM-12. Together these results provide a foundation for therapeutic down-regulation of ADAM-12 in cancer, arthritis and cardiac hypertrophy. gene regulation | repressor proteins | pathogenesis doi/ 10.1073/pnas.1008831108
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