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Cisplatin binds hum...
Cisplatin binds human copper chaperone Atox1 and promotes unfolding in vitro.
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Palm, Maria E (författare)
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- Weise, Christoph F (författare)
- Umeå universitet,Kemiska institutionen
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- Lundin, Christina, 1970- (författare)
- Umeå universitet,Kirurgi
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- Wingsle, Gunnar (författare)
- Swedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för skoglig genetik och växtfysiologi,Department of Forest Genetics and Plant Physiology
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- Nygren, Yvonne (författare)
- Umeå universitet,Kemiska institutionen
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- Björn, Erik (författare)
- Umeå universitet,Kemiska institutionen
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- Naredi, Peter, 1955- (författare)
- Umeå universitet,Kirurgi
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- Wolf-Watz, Magnus (författare)
- Umeå universitet,Kemiska institutionen
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- Wittung Stafshede, Pernilla, 1968 (författare)
- Umeå universitet,Kemiska institutionen
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(creator_code:org_t)
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- 2011-04-11
- 2011
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 108:17, s. 6951-6
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http://dx.doi.org/10...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- Cisplatin (cisPt), Pt(NH(3))(2)Cl(2), is a cancer drug believed to kill cells via DNA binding and damage. Recent work has implied that the cellular copper (Cu) transport machinery may be involved in cisPt cell export and drug resistance. Normally, the Cu chaperone Atox1 binds Cu(I) via two cysteines and delivers the metal to metal-binding domains of ATP7B; the ATP7B domains then transfer the metal to the Golgi lumen for loading on cuproenzymes. Here, we use spectroscopic methods to test if cisPt interacts with purified Atox1 in solution in vitro. We find that cisPt binds to Atox1's metal-binding site regardless of the presence of Cu or not: When Cu is bound to Atox1, the near-UV circular dichroism signals indicate Cu-Pt interactions. From NMR data, it is evident that cisPt binds to the folded protein. CisPt-bound Atox1 is however not stable over time and the protein begins to unfold and aggregate. The reaction rates are limited by slow cisPt dechlorination. CisPt-induced unfolding of Atox1 is specific because this effect was not observed for two unrelated proteins that also bind cisPt. Our study demonstrates that Atox1 is a candidate for cisPt drug resistance: By binding to Atox1 in the cytoplasm, cisPt transport to DNA may be blocked. In agreement with this model, cell line studies demonstrate a correlation between Atox1 expression levels, and cisplatin resistance.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
- LANTBRUKSVETENSKAPER -- Lantbruksvetenskap, skogsbruk och fiske -- Skogsvetenskap (hsv//swe)
- AGRICULTURAL SCIENCES -- Agriculture, Forestry and Fisheries -- Forest Science (hsv//eng)
Nyckelord
- Humans
- genetics
- Protein Binding
- Copper
- metabolism
- DNA
- Cation Transport Proteins
- Biological Transport
- pharmacokinetics
- chemistry
- chemistry
- Antineoplastic Agents
- genetics
- drug effects
- metabolism
- Binding Sites
- metabolism
- Neoplasms
- Drug Resistance
- Molecular Chaperones
- chemistry
- chemistry
- Neoplasm
- Protein Structure
- Cisplatin
- metabolism
- Tertiary
- drug effects
- pharmacokinetics
- drug effects
- Protein Folding
- drug therapy
- metabolism
- chemistry
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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