NDLI: Quantitative proteomics reveals that Hsp90 inhibition preferentially targets kinases and the DNA damage response.

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Year: 2012 Volume: 11 Issue: 2

Year: 2012 Volume: 11 Issue: 1

Year: 2011 Volume: 10

Quantitative proteomics reveals that Hsp90 inhibition preferentially targets kinases and the DNA damage response.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Sharma, Kirti Vabulas, R. Martin Macek, Boris Pinkert, Stefan Cox, Jürgen Mann, Matthias Hartl, F. Ulrich
Description	Country affiliation: Germany Author Affiliation: Sharma K ( Departments of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.)
Abstract	Despite the increasing importance of heat shock protein 90 (Hsp90) inhibitors as chemotherapeutic agents in diseases such as cancer, their global effects on the proteome remain largely unknown. Here we use high resolution, quantitative mass spectrometry to map protein expression changes associated with the application of the Hsp90 inhibitor, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG). In depth data obtained from five replicate SILAC experiments enabled accurate quantification of about 6,000 proteins in HeLa cells. As expected, we observed activation of a heat shock response with induced expression of molecular chaperones, which refold misfolded proteins, and proteases, which degrade irreparably damaged polypeptides. Despite the broad range of known Hsp90 substrates, bioinformatics analysis revealed that particular protein classes were preferentially affected. These prominently included proteins involved in the DNA damage response, as well as protein kinases and especially tyrosine kinases. We followed up on this observation with a quantitative phosphoproteomic analysis of about 4,000 sites, which revealed that Hsp90 inhibition leads to much more down- than up-regulation of the phosphoproteome (34% down versus 6% up). This study defines the cellular response to Hsp90 inhibition at the proteome level and sheds light on the mechanisms by which it can be used to target cancer cells.
File Format	HTM / HTML
ISSN	15359476
e-ISSN	15359484
DOI	10.1074/mcp.M111.014654
Journal	Molecular & Cellular Proteomics
Issue Number	3
Volume Number	11
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	2012-03-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Discipline Proteomics Benzoquinones Pharmacology Dna Damage Drug Effects Hsp90 Heat-shock Proteins Antagonists & Inhibitors Lactams, Macrocyclic Protein-tyrosine Kinases Metabolism Proteome Proteomics Computational Biology Hela Cells Molecular Chaperones Phosphopeptides Protein Folding Spectrometry, Mass, Matrix-assisted Laser Desorption-ionization Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Medicine Analytical Chemistry Molecular Biology Biochemistry

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Systematic Identification of the HSP90 Regulated Proteome

Quantitative Proteomics Reveals That Hsp90 Inhibition Preferentially Targets Kinases and the DNA Damage Response*

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