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Molecular and Cellular Biology, May 2005, p. 3715-3725, Vol. 25, No. 9
0270-7306/05/$08.00+0 doi:10.1128/MCB.25.9.3715-3725.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.
Sundar Ganesan,2,
Christoph P. Dohm,1
Stan Krajewski,3
John C. Reed,3
Mathias Bähr,1
Fred S. Wouters,2*,
and
Pawel Kermer1*,
Neurologische Klinik, Universität Göttingen,1 Cell Biophysics Group, European Neuroscience Institute Göttingen, Göttingen, Germany,2 The Burnham Institute, La Jolla, California3
Received 17 September 2004/ Returned for modification 20 October 2004/ Accepted 19 January 2005
It was recently shown that Bcl-2-associated athanogene 1 (BAG1) is a potent neuroprotectant as well as a marker of neuronal differentiation. Since there appears to exist an equilibrium within the cell between BAG1 binding to heat shock protein 70 (Hsp70) and BAG1 binding to Raf-1 kinase, we hypothesized that changing BAG1 binding characteristics might significantly alter BAG1 function. To this end, we compared rat CSM14.1 cells and human SHSY-5Y cells stably overexpressing full-length BAG1 or a deletion mutant (BAG
C) no longer capable of binding to Hsp70. Using a novel yellow fluorescent protein-based foldase biosensor, we demonstrated an upregulation of chaperone in situ activity in cells overexpressing full-length BAG1 but not in cells overexpressing BAG
C compared to wild-type cells. Interestingly, in contrast to the nuclear and cytosolic localizations of full-length BAG1, BAG
C was expressed exclusively in the cytosol. Furthermore, cells expressing BAG
C were no longer protected against cell death. However, they still showed accelerated neuronal differentiation. Together, these results suggest that BAG1-induced activation of Hsp70 is important for neuroprotectivity, while BAG1-dependent modulation of neuronal differentiation in vitro is not.
* Corresponding author. Mailing address for Pawel Kermer: Neurologische Klinik, Universität Göttingen, Robert-Koch-Str. 40, 37075 Göttingen, Germany. Phone: 49-551-394927. Fax: 49-551-3914302. E-mail: pkermer{at}gwdg.de.
Supplemental material for this article may be found at http://mcb.asm.org/.
J.L., S.G., F.S.W., and P.K. contributed equally to this work.
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