Document Detail


CD47 deficiency confers cell and tissue radioprotection by activation of autophagy.
MedLine Citation:
PMID:  22874555     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Accidental or therapeutic exposure to ionizing radiation has severe physiological consequences and can result in cell death. We previously demonstrated that deficiency or blockade of the ubiquitously expressed receptor CD47 results in remarkable cell and tissue protection against ischemic and radiation stress. Antagonists of CD47 or its ligand THBS1/thrombospondin 1 enhance cell survival and preserve their proliferative capacity. However the signaling pathways that mediate this cell-autonomous radioprotection are unclear. We now report a marked increase in autophagy in irradiated T-cells and endothelial cells lacking CD47. Irradiated T cells lacking CD47 exhibit significant increases in formation of autophagosomes comprising double-membrane vesicles visualized by electron microscopy and numbers of MAP1LC3A/B(+) puncta. Moreover, we observed significant increases in BECN1, ATG5, ATG7 and a reduction in SQSTM1/p62 expression relative to irradiated wild-type T cells. We observed similar increases in autophagy gene expression in mice resulting from blockade of CD47 in combination with total body radiation. Pharmacological or siRNA-mediated inhibition of autophagy selectively sensitized CD47-deficient cells to radiation, indicating that enhanced autophagy is necessary for the prosurvival response to CD47 blockade. Moreover, re-expression of CD47 in CD47-deficient T cells sensitized these cells to death by ionizing radiation and reversed the increase in autophagic flux associated with survival. This study indicates that CD47 deficiency confers cell survival through the activation of autophagic flux and identifies CD47 blockade as a pharmacological route to modulate autophagy for protecting tissue from radiation injury.
Authors:
David R Soto-Pantoja; Thomas W Miller; Michael L Pendrak; William G DeGraff; Camille Sullivan; Lisa A Ridnour; Mones Abu-Asab; David A Wink; Maria Tsokos; David D Roberts
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural     Date:  2012-08-09
Journal Detail:
Title:  Autophagy     Volume:  8     ISSN:  1554-8635     ISO Abbreviation:  Autophagy     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2013-01-25     Completed Date:  2013-07-10     Revised Date:  2013-11-06    
Medline Journal Info:
Nlm Unique ID:  101265188     Medline TA:  Autophagy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1628-42     Citation Subset:  IM    
Affiliation:
Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
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MeSH Terms
Descriptor/Qualifier:
Adaptor Proteins, Signal Transducing / metabolism
Animals
Antigens, CD47 / genetics*,  metabolism*
Apoptosis / radiation effects
Apoptosis Regulatory Proteins / genetics,  metabolism
Autophagy* / genetics
Gene Expression Regulation / radiation effects
Gene Silencing / radiation effects
Human Umbilical Vein Endothelial Cells / cytology,  metabolism,  radiation effects
Humans
Jurkat Cells
Membrane Proteins / genetics,  metabolism
Mice
Mice, Inbred C57BL
Microtubule-Associated Proteins / genetics,  metabolism
Organ Specificity / radiation effects*
Phagosomes / metabolism,  ultrastructure
Radiation Protection*
Radiation, Ionizing
Ubiquitin-Activating Enzymes / genetics,  metabolism
Up-Regulation / radiation effects
Whole-Body Irradiation
Chemical
Reg. No./Substance:
0/ATG5 protein, human; 0/Adaptor Proteins, Signal Transducing; 0/Antigens, CD47; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Membrane Proteins; 0/Microtubule-Associated Proteins; 0/SQSTM1 protein, human; 0/light chain 3, human; EC 6.3.2.19/Atg7 protein, human; EC 6.3.2.19/Ubiquitin-Activating Enzymes
Comments/Corrections

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