title: Specificity protein 1 (sp1) oscillation is involved in copper homeostasis maintenance by regulating human high-affinity copper transporter 1 expression.
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.
authors.affiliation: Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA.
authors.forename: Zheng D
authors.initials: ZD
authors.lastname: Liang
authors.forename: Wen-Bin
authors.initials: WB
authors.lastname: Tsai
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Lee
authors.forename: Niramol
authors.initials: N
authors.lastname: Savaraj
authors.forename: Macus Tien
authors.initials: MT
authors.lastname: Kuo
mesh_terms: D015153:Blotting, Western; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D015536:Down-Regulation; D006706:Homeostasis / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D016329:Sp1 Transcription Factor / Q000502:physiology*; D014158:Transcription, Genetic; D015854:Up-Regulation; D016335:Zinc Fingers
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D016329:Sp1 Transcription Factor; D003300:Copper