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Genes Dev. 2015 Oct 1;29(19):2010-21. doi: 10.1101/gad.269118.115. Epub 2015 Sep 24.

Aneuploidy-induced cellular stresses limit autophagic degradation.

Author information

1
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02138, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02138, USA; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02138, USA;
2
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02138, USA;
3
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08903-2681 USA.

Abstract

An unbalanced karyotype, a condition known as aneuploidy, has a profound impact on cellular physiology and is a hallmark of cancer. Aneuploid cells experience a number of stresses that are caused by aneuploidy-induced proteomic changes. How the aneuploidy-associated stresses affect cells and whether cells respond to them are only beginning to be understood. Here we show that autophagosomal cargo such as protein aggregates accumulate within lysosomes in aneuploid cells. This causes a lysosomal stress response. Aneuploid cells activate the transcription factor TFEB, a master regulator of autophagic and lysosomal gene expression, thereby increasing the expression of genes needed for autophagy-mediated protein degradation. Accumulation of autophagic cargo within the lysosome and activation of TFEB-responsive genes are also observed in cells in which proteasome function is inhibited, suggesting that proteotoxic stress causes TFEB activation. Our results reveal a TFEB-mediated lysosomal stress response as a universal feature of the aneuploid state.

KEYWORDS:

TFEB; aneuploidy; autophagy; cancer; proteotoxicity

PMID:
26404941
PMCID:
PMC4604343
DOI:
10.1101/gad.269118.115
[Indexed for MEDLINE]
Free PMC Article

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