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  HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells

Donnelly, N., Passerini, V., Dürrbaum, M., Stingele, S., & Storchova, Z. (2014). HSF1 deficiency and impaired HSP90-dependent protein folding are hallmarks of aneuploid human cells. EMBO JOURNAL, 33(20), 2374-2387. doi:10.15252/embj.201488648.

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 Creators:
Donnelly, Neysan1, Author              
Passerini, Verena1, Author              
Dürrbaum, Milena1, Author              
Stingele, Silvia1, Author              
Storchova, Zuzana1, Author              
Affiliations:
1Storchova, Zuzana / Maintenance of Genome Stability, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565171              

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Free keywords: HEAT-SHOCK FACTOR-1; CANCER-CELLS; CO-CHAPERONES; HSP90; STRESS; YEAST; INSTABILITY; GENOME; HSP70; TRANSCRIPTOMEaneuploidy; cancer; HSF1; HSP90; protein folding;
 Abstract: Aneuploidy is a hallmark of cancer and is associated with malignancy and poor prognosis. Recent studies have revealed that aneuploidy inhibits proliferation, causes distinct alterations in the transcriptome and proteome and disturbs cellular proteostasis. However, the molecular mechanisms underlying the changes in gene expression and the impairment of proteostasis are not understood. Here, we report that human aneuploid cells are impaired in HSP90-mediated protein folding. We show that aneuploidy impairs induction of the heat shock response suggesting that the activity of the transcription factor heat shock factor 1 (HSF1) is compromised. Indeed, increased levels of HSF1 counteract the effects of aneuploidy on HSP90 expression and protein folding, identifying HSF1 overexpression as the first aneuploidy-tolerating mutation in human cells. Thus, impaired HSF1 activity emerges as a critical factor underlying the phenotypes linked to aneuploidy. Finally, we demonstrate that deficient protein folding capacity directly shapes gene expression in aneuploid cells. Our study provides mechanistic insight into the causes of the disturbed proteostasis in aneuploids and deepens our understanding of the role of HSF1 in cytoprotection and carcinogenesis.

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Language(s): eng - English
 Dates: 2014
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000343922500010
DOI: 10.15252/embj.201488648
 Degree: -

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Title: EMBO JOURNAL
Source Genre: Journal
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Publ. Info: 111 RIVER ST, HOBOKEN 07030-5774, NJ USA : WILEY-BLACKWELL
Pages: - Volume / Issue: 33 (20) Sequence Number: - Start / End Page: 2374 - 2387 Identifier: ISSN: 0261-4189