Cellular up-regulation of Nedd4 family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes

Schieber, Christine, Howitt, Jason, Putz, Ulrich, White, Jonathan M., Parish, Clare L., Donnelly, Paul S. and Tan, Seong-Seng (2011) Cellular up-regulation of Nedd4 family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes. Journal of Biological Chemistry, 286 10: 8555-8564. doi:10.1074/jbc.M110.203448

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Author Schieber, Christine
Howitt, Jason
Putz, Ulrich
White, Jonathan M.
Parish, Clare L.
Donnelly, Paul S.
Tan, Seong-Seng
Title Cellular up-regulation of Nedd4 family interacting protein 1 (Ndfip1) using low levels of bioactive cobalt complexes
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
Publication date 2011-03-11
Sub-type Article (original research)
DOI 10.1074/jbc.M110.203448
Open Access Status File (Publisher version)
Volume 286
Issue 10
Start page 8555
End page 8564
Total pages 10
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Formatted abstract
The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co III(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl2 that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic CoIII complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of CoIII to CoII leading to release of CoII ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co III complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of CoIII complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Queensland Brain Institute Publications
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Citation counts: TR Web of Science Citation Count  Cited 7 times in Thomson Reuters Web of Science Article | Citations
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Created: Mon, 27 Oct 2014, 17:10:46 EST by Sylvie Pichelin on behalf of Queensland Brain Institute