Document Detail


ER stress-mediated autophagy promotes Myc-dependent transformation and tumor growth.
MedLine Citation:
PMID:  23143306     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The proto-oncogene c-Myc paradoxically activates both proliferation and apoptosis. In the pathogenic state, c-Myc-induced apoptosis is bypassed via a critical, yet poorly understood escape mechanism that promotes cellular transformation and tumorigenesis. The accumulation of unfolded proteins in the ER initiates a cellular stress program termed the unfolded protein response (UPR) to support cell survival. Analysis of spontaneous mouse and human lymphomas demonstrated significantly higher levels of UPR activation compared with normal tissues. Using multiple genetic models, we demonstrated that c-Myc and N-Myc activated the PERK/eIF2α/ATF4 arm of the UPR, leading to increased cell survival via the induction of cytoprotective autophagy. Inhibition of PERK significantly reduced Myc-induced autophagy, colony formation, and tumor formation. Moreover, pharmacologic or genetic inhibition of autophagy resulted in increased Myc-dependent apoptosis. Mechanistically, we demonstrated an important link between Myc-dependent increases in protein synthesis and UPR activation. Specifically, by employing a mouse minute (L24+/-) mutant, which resulted in wild-type levels of protein synthesis and attenuation of Myc-induced lymphomagenesis, we showed that Myc-induced UPR activation was reversed. Our findings establish a role for UPR as an enhancer of c-Myc-induced transformation and suggest that UPR inhibition may be particularly effective against malignancies characterized by c-Myc overexpression.
Authors:
Lori S Hart; John T Cunningham; Tatini Datta; Souvik Dey; Feven Tameire; Stacey L Lehman; Bo Qiu; Haiyan Zhang; George Cerniglia; Meixia Bi; Yan Li; Yan Gao; Huayi Liu; Changhong Li; Amit Maity; Andrei Thomas-Tikhonenko; Alexander E Perl; Albert Koong; Serge Y Fuchs; J Alan Diehl; Ian G Mills; Davide Ruggero; Constantinos Koumenis
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2013-08-15    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4621-34     Citation Subset:  AIM; IM    
Affiliation:
Department of Radiation Oncology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-5156, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis
Autophagy*
Burkitt Lymphoma / metabolism*,  pathology
Calcium Signaling
Caspases / metabolism
Cell Line, Tumor
Cell Proliferation
Cell Survival
Cell Transformation, Neoplastic / metabolism*
Cluster Analysis
Endoplasmic Reticulum Stress
Gene Knockout Techniques
Heterozygote
Humans
Mice
Oligonucleotide Array Sequence Analysis
Proto-Oncogene Proteins c-myc / metabolism,  physiology*
Ribosomal Proteins / genetics,  metabolism
Transcriptome
Unfolded Protein Response
eIF-2 Kinase / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
P01 CA104838/CA/NCI NIH HHS; P01CA104838/CA/NCI NIH HHS; R01 CA092900/CA/NCI NIH HHS; R01 CA140456/CA/NCI NIH HHS; R01 CA142425/CA/NCI NIH HHS; R01CA094214/CA/NCI NIH HHS; R01CA122334/CA/NCI NIH HHS; R01CA139362/CA/NCI NIH HHS; R01CA140456/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/MYC protein, human; 0/Proto-Oncogene Proteins c-myc; 0/Ribosomal Proteins; 0/ribosomal protein L24; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/eIF-2 Kinase; EC 3.4.22.-/Caspases
Comments/Corrections

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