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Research ArticleArticle

Specificity Protein 1 (Sp1) Oscillation Is Involved in Copper Homeostasis Maintenance by Regulating Human High-Affinity Copper Transporter 1 Expression

Zheng D. Liang, Wen-Bin Tsai, Mei-Yi Lee, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology March 2012, 81 (3) 455-464; DOI: https://doi.org/10.1124/mol.111.076422
Zheng D. Liang
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Wen-Bin Tsai
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Mei-Yi Lee
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Niramol Savaraj
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Macus Tien Kuo
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Abstract

Copper is an essential micronutrient for cell growth but is toxic in excess. Copper transporter (Ctr1) plays an important role in regulating adequate copper levels in mammalian cells. We have shown previously that expression of the human high-affinity copper transporter (hCtr1) was transcriptionally up-regulated under copper-depleted conditions and down-regulated under replete conditions; moreover, elevated hCtr1 levels suppress hCtr1 expression. Specificity protein 1 (Sp1) regulates expression of hCtr1 under copper-stressed conditions. In this study, we made the following important observations: 1) Sp1 expression is down-regulated under copper-replete conditions but up-regulated under copper-depleted conditions. These up- and down-regulations of Sp1 in turn regulate hCtr1 expression to control copper homeostasis. 2) Copper-regulated Sp1 expression involved Sp1 binding to its own promoter as demonstrated by the chromatin immunoprecipitation assay; therefore, Sp1 is also transcriptionally self-regulated via hCtr1/copper intermediation. 3) Both zinc finger and glutamine-rich transactivation domains of Sp1 are involved in the Sp1-mediated hCtr1 and Sp1 regulation by copper stresses. 4) Although Sp3 expression is also regulated by copper availability, Sp3 does not regulate hCtr1 homeostasis. Collectively, our results demonstrated that mammalian cells use Sp1 oscillation in response to copper availability to regulate copper homeostasis through hCtr1 expression in a tripartite inter-regulatory relationship. These findings have important implications in mammalian copper physiology regulation.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • This work was supported by the National Institutes of Health National Cancer Institute [Grants R01-CA149620, CA16672].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.111.076422.

  • ABBREVIATIONS:

    Ctr
    copper transporter
    hCtr1
    human high-affinity copper transporter 1
    DN
    dominant negative
    Sp1
    specificity protein 1
    SCLC
    small-cell lung cancer
    TM
    tetrathiomolybdate
    DBD
    DNA-binding domain
    TAD
    transactivating domain
    PCR
    polymerase chain reaction
    ChIP
    chromatin immunoprecipitation
    RPA
    RNase protection assay
    TM
    tetrathiomolybdate
    siRNA
    small interfering RNA
    wt
    wild type
    endo
    endogenous
    exo
    exogenous
    HEK
    human embryonic kidney
    ZF
    zinc finger
    KLF
    Krüppel-like factor
    HA
    hemagglutinin.

  • Received October 17, 2011.
  • Accepted December 15, 2011.
  • U.S. Government work not protected by U.S. copyright
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Molecular Pharmacology: 81 (3)
Molecular Pharmacology
Vol. 81, Issue 3
1 Mar 2012
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Research ArticleArticle

Regulation of Copper Homeostasis in Human Cells

Zheng D. Liang, Wen-Bin Tsai, Mei-Yi Lee, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology March 1, 2012, 81 (3) 455-464; DOI: https://doi.org/10.1124/mol.111.076422

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Research ArticleArticle

Regulation of Copper Homeostasis in Human Cells

Zheng D. Liang, Wen-Bin Tsai, Mei-Yi Lee, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology March 1, 2012, 81 (3) 455-464; DOI: https://doi.org/10.1124/mol.111.076422
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