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ToxSci Advance Access originally published online on June 20, 2007
Toxicological Sciences 2007 99(1):267-276; doi:10.1093/toxsci/kfm158
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Perturbation of Copper (Cu) Homeostasis and Expression of Cu-Binding Proteins in Cadmium-Resistant Lung Fibroblasts

Denise K. Chou*, Yinzhi Zhao*, Song Gao*, Iih-Nan Chou{dagger}, Paul Toselli*, Phillip Stone* and Wande Li*,1

* Department of Biochemistry {dagger} Department of Microbiology, Boston University School of Medicine, 715 Albany Street, Boston, Massachusetts 02118

1 To whom correspondence should be addressed. Fax: (617) 638-5339. E-mail: wandeli{at}bu.edu.

Received May 21, 2007; accepted June 8, 2007


  Abstract

To probe mechanisms of cadmium (Cd) damage to the lung extracellular matrix (ECM), we developed Cd-resistant (CdR) rat lung fibroblasts (RFL6) by incubation with graded concentrations of Cd. CdR cells downregulated lysyl oxidase (LO), a copper (Cu)-dependent enzyme essential for crosslinking of collagen and elastin in the ECM, in conjunction with upregulation of other Cu-binding proteins including Cu,Zn-superoxide dismutase (SOD1), copper chaperone for SOD1 (CCS1), metallothionein (MT), and Menkes P-type ATPase (ATP7A), a Cu transporter in the membrane of the Golgi apparatus, as well as {gamma}-glutamylcysteine synthetase ({gamma}-GCS), an enzyme for glutathione biosynthesis. Reduction and loss of cytoplasmic distribution of LO in CdR cells were accompanied by its dislocation with the Menkes P-type ATPase and the endoplasmic reticulum marker. CdR cells displayed a defect in LO catalytic activity but an enhancement in Cu,Zn-SOD catalytic activity consistent with the protein expression levels of these enzymes. Although long-term Cd exposure of cells enhanced the Menkes P-type ATPase protein expression, actually, it reduced Cu-dependent catalytic activity of this enzyme in parallel with the deficiency of LO. The low level of 64Cu bound to the LO fraction and the high level of 64Cu bound to the MT fraction provide direct evidence for limitation of Cu bioavailability for LO existing in the CdR cells. These results suggest that downregulation of LO is linked with upregulation of other Cu-binding proteins and with alteration in Cu homeostasis in the CdR phenotype.

Key Words: lysyl oxidase; cadmium; copper; metallothionein; Menkes P-type ATPase; copper-binding proteins.


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