Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
OtherArticle

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Zheng D. Liang, David Stockton, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology October 2009, 76 (4) 843-853; DOI: https://doi.org/10.1124/mol.109.056416
Zheng D. Liang
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Stockton
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Niramol Savaraj
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Macus Tien Kuo
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The human high-affinity copper transporter (hCtr1) plays an important role in the regulation of intracellular copper homeostasis. hCtr1 is involved in the transport of platinum-based antitumor agents such as cisplatin (CDDP); however, the mechanisms that regulate hCtr1-mediated transport of these agents have not been well elucidated. We compared the mechanisms of hCtr1-mediated transport of copper and CDDP. We found that replacements of several methionine residues that are essential for hCtr1-mediated copper transport conferred a dominant-negative effect on the endogenous hCtr1’s function, resulting in reduced rates of Cu(I) and CDDP transport and increased resistance to the toxicities of copper and CDDP treatments. Kinetic constant analyses revealed that although these mutations reduced maximal transport rates (Vmax) for Cu(I) and CDDP, reduction of Km only for Cu(I) but not for CDDP was observed. Mutation in Gly167, which is located in the third transmembrane domain and is involved in helix packing of hCtr1, also conferred dominant-negative property of Cu(I) transport but not of CDDP transport. Deleting the N-terminal 45 amino acids that contain two methionine-rich motifs resulted in cytoplasmic localization of the hCtr1 and abolished the dominant-negative function of these mutants. Nonetheless, these mutations did not affect the capacities of hCtr1 oligomerization induced by copper or CDDP, suggesting a distinct structural requirement between metal transport and oligomerization. Finally, we also observed that expressing the dominant-negative hCtr1 mutants up-regulates endogenous hCtr1 mRNA expression, consistent with our previous report that intracellular copper homeostasis and homeostatic levels of hCtr1 mRNA are mutually regulated.

  • TM, transmembrane domain
  • wt, wild-type
  • BS3, bis(sulfosuccinimidyl)suberate
  • CDDP, cisplatin [
  • cis-diamminedichloroplatinum(II)]; hCtr1, human high-affinity copper transporter 1
  • FRET, fluorescence resonance energy transfer
  • SCLC, small-cell lung cancer
  • HA, hemagglutinin.

Footnotes

  • This study was supported in part by the National Institutes of Health National Cancer Institute [Grants R01-CA79085, R01-CA89541, R01-CA16672] and the Veterans Administration Merit Research Fund.

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

  • ABBREVIATIONS:

    • Received March 25, 2009.
    • Accepted June 30, 2009.
  • © 2009 The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 76 (4)
Molecular Pharmacology
Vol. 76, Issue 4
October 2009
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Back Matter (PDF)
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
OtherArticle

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Zheng D. Liang, David Stockton, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology October 1, 2009, 76 (4) 843-853; DOI: https://doi.org/10.1124/mol.109.056416

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
OtherArticle

Mechanistic Comparison of Human High-Affinity Copper Transporter 1-Mediated Transport between Copper Ion and Cisplatin

Zheng D. Liang, David Stockton, Niramol Savaraj and Macus Tien Kuo
Molecular Pharmacology October 1, 2009, 76 (4) 843-853; DOI: https://doi.org/10.1124/mol.109.056416
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • P2X7 Positive Modulator Structure-Activity Relationship
  • Predicting Drug Interactions with ENT1 and ENT2
  • GABAAR Molecular Identity in Oligodendrocytes
Show more Articles

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics