Gene expression profiling of liver cells after copper overload in vivo and in vitro reveals new copper-regulated genes

被引:71
作者
Muller, Patricia
van Bakel, Harm
van de Sluis, Bart
Holstege, Frank
Wijmenga, Cisca
Klomp, Leo W. J. [1 ]
机构
[1] Univ Utrecht, Med Ctr, Lab Metabol & Endocrine Dis, Utrecht, Netherlands
[2] Univ Utrecht, Med Ctr, DBG Dept Med Genet, Complex Genet Sect, Utrecht, Netherlands
[3] Univ Utrecht, Med Ctr, Genom Lab, Utrecht, Netherlands
[4] NHGRI, Oncogenesis & Dev Sect, NIH, Bethesda, MD 20892 USA
[5] Wilhelmina Childrens Hosp, Lab Metab & Endocrine Dis, NL-3584 EA Utrecht, Netherlands
来源
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY | 2007年 / 12卷 / 04期
关键词
copper; liver; microarray; gene expression; HepG2;
D O I
10.1007/s00775-006-0201-y
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Copper toxicity in the liver is mediated by free-radical generation, resulting in oxidative stress. To prevent toxic accumulation of copper, liver cells adapt to high copper levels. Here, we used microarray analysis to compare the adaptive responses on global gene expression in liver cells exposed to high copper levels in vitro and in vivo. In HepG2 cells we identified two clusters of upregulated genes over time, an "early" cluster that comprised metallothionein genes and a "late" cluster, highly enriched in genes involved in proteasomal degradation and in oxidative stress response. Concomitant with the "late" cluster, we detected a significant downregulation of several copper metabolism MURR1 domain (COMMD) genes that were recently implicated in copper metabolism and inhibition of nuclear transcription factor kappa B (NF-kappa B) signaling. As metal-induced oxidative stress increases NF-kappa B activity, our data suggest a role for reduced COMMD protein levels in prolonged activation of NF-kappa B, thus inducing cell survival. Mice exposed to a copper diet that highly exceeded normal daily intake accumulated only twofold more hepatic copper than control mice. Although a moderate, but significant upregulation of a set of 22 genes involved in immunity, iron and cholesterol metabolism was detected, these cannot account for direct mechanisms involved in copper excretion. In conclusion, we identified a novel set of genes that represent a delayed response to copper overload, thus providing insight into the adaptive transcriptional response to copper-induced oxidative stress.
引用
收藏
页码:495 / 507
页数:13
相关论文
共 42 条
[11]   Yeast, a model organism for iron and copper metabolism studies [J].
De Freitas, J ;
Wintz, H ;
Kim, JH ;
Poynton, H ;
Fox, T ;
Vulpe, C .
BIOMETALS, 2003, 16 (01) :185-197
[12]   Exploratory and confirmatory gene expression profiling of mac1Δ [J].
De Freitas, JM ;
Kim, JH ;
Poynton, H ;
Su, T ;
Wintz, H ;
Fox, T ;
Holman, P ;
Loguinov, A ;
Keles, S ;
van der Laan, M ;
Vulpe, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (06) :4450-4458
[13]   Induction of nuclear factor kappa B by the CD30 receptor is mediated by TRAF1 and TRAF2 [J].
Duckett, CS ;
Gedrich, RW ;
Gilfillan, MC ;
Thompson, CB .
MOLECULAR AND CELLULAR BIOLOGY, 1997, 17 (03) :1535-1542
[14]  
Fuentealba I Carmen, 2003, Comp Hepatol, V2, P5, DOI 10.1186/1476-5926-2-5
[15]   Bioconductor: open software development for computational biology and bioinformatics [J].
Gentleman, RC ;
Carey, VJ ;
Bates, DM ;
Bolstad, B ;
Dettling, M ;
Dudoit, S ;
Ellis, B ;
Gautier, L ;
Ge, YC ;
Gentry, J ;
Hornik, K ;
Hothorn, T ;
Huber, W ;
Iacus, S ;
Irizarry, R ;
Leisch, F ;
Li, C ;
Maechler, M ;
Rossini, AJ ;
Sawitzki, G ;
Smith, C ;
Smyth, G ;
Tierney, L ;
Yang, JYH ;
Zhang, JH .
GENOME BIOLOGY, 2004, 5 (10)
[16]   Identification of the copper regulon in Saccharomyces cerevisiae by DNA microarrays [J].
Gross, C ;
Kelleher, M ;
Iyer, VR ;
Brown, PO ;
Winge, DR .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (41) :32310-32316
[17]   THE TRANSCRIPTION FACTOR MTF-1 IS ESSENTIAL FOR BASAL AND HEAVY METAL-INDUCED METALLOTHIONEIN GENE-EXPRESSION [J].
HEUCHEL, R ;
RADTKE, F ;
GEORGIEV, O ;
STARK, G ;
AGUET, M ;
SCHAFFNER, W .
EMBO JOURNAL, 1994, 13 (12) :2870-2875
[18]  
Huber Wolfgang, 2002, Bioinformatics, V18 Suppl 1, pS96
[19]   Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages [J].
Ishii, T ;
Itoh, K ;
Takahashi, S ;
Sato, H ;
Yanagawa, T ;
Katoh, Y ;
Bannai, S ;
Yamamoto, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (21) :16023-16029
[20]  
Kleinman MH, 2003, PHOTOCHEM PHOTOBIOL, V77, P10, DOI 10.1562/0031-8655(2003)077<0010:TSON>2.0.CO