Autophagy Controls CSL/RBPJκ Stability through a p62/SQSTM1-Dependent Mechanism.

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State: Public
Version: Final published version
Serval ID
serval:BIB_4A74051ADE12
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Autophagy Controls CSL/RBPJκ Stability through a p62/SQSTM1-Dependent Mechanism.
Journal
Cell reports
Author(s)
Goruppi S., Jo S.H., Laszlo C., Clocchiatti A., Neel V., Dotto G.P.
ISSN
2211-1247 (Electronic)
Publication state
Published
Issued date
18/09/2018
Peer-reviewed
Oui
Volume
24
Number
12
Pages
3108-3114.e4
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Cancer-associated fibroblasts (CAFs) are important at all tumor stages. CSL/RBPJκ suppresses the gene expression program leading to CAF activation and associated metabolic reprogramming, as well as autophagy. Little is known about CSL protein turnover, especially in the tumor microenvironment. We report that, in human dermal fibroblasts (HDFs), conditions inducing autophagy-often found in tumor stroma-down-regulate CSL protein levels but do not affect its mRNA levels. Genetic or pharmacologic targeting of the autophagic machinery blocks CSL down-modulation. Mechanistically, endogenous CSL associates with the autophagy and signaling adaptor p62/SQSTM1, which is required for CSL down-modulation by autophagy. This is functionally significant, because both CSL and p62 levels are lower in skin cancer-derived CAFs, in which autophagy is increased. Increasing cellular CSL levels stabilizes p62 and down-modulates the autophagic process. We reveal here an autophagy-initiated mechanism for CSL down-modulation, which could be targeted for stroma-focused cancer prevention and treatment.
Keywords
CAF, CSL/RBPJκ, autophagy, cancer-associated fibroblast, p62/SQSTM1, protein turnover
Pubmed
Web of science
Open Access
Yes
Create date
08/10/2018 9:01
Last modification date
20/08/2019 14:58
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