Document Detail


Epidermal growth factor receptor vIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation.
MedLine Citation:
PMID:  18337449     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Little is known about the factors that influence the proteasome structures in cells and their activity, although this could be highly relevant to cancer therapy. We have previously shown that, within minutes, irradiation inhibits substrate degradation by the 26S proteasome in most cell types. Here, we report an exception in U87 glioblastoma cells transduced to express the epidermal growth factor receptor vIII (EGFRvIII) mutant (U87EGFRvIII), which does not respond to irradiation with 26S proteasome inhibition. This was assessed using either a fluorogenic substrate or a reporter gene, the ornithine decarboxylase degron fused to ZsGreen (cODCZsGreen), which targets the protein to the 26S proteasome. To elucidate whether this was due to alterations in proteasome composition, we used quantitative reverse transcription-PCR to quantify the constitutive (X, Y, Z) and inducible 20S subunits (Lmp7, Lmp2, Mecl1), and 11S (PA28alpha and beta) and 19S components (PSMC1 and PSMD4). U87 and U87EGFRvIII significantly differed in expression of proteasome subunits, and in particular immunosubunits. Interestingly, 2 Gy irradiation of U87 increased subunit expression levels by 16% to 324% at 6 hours, with a coincident 30% decrease in levels of the proteasome substrate c-myc, whereas they changed little in U87EGFRvIII. Responses similar to 2 Gy were seen in U87 treated with a proteasome inhibitor, NPI0052, suggesting that proteasome inhibition induced replacement of subunits independent of the means of inhibition. Our data clearly indicate that the composition and function of the 26S proteasome can be changed by expression of the EGFRvIII. How this relates to the increased radioresistance associated with this cell line remains to be established.
Authors:
Kwanghee Kim; James M Brush; Philip A Watson; Nicholas A Cacalano; Keisuke S Iwamoto; William H McBride
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Molecular cancer research : MCR     Volume:  6     ISSN:  1541-7786     ISO Abbreviation:  Mol. Cancer Res.     Publication Date:  2008 Mar 
Date Detail:
Created Date:  2008-03-13     Completed Date:  2008-06-03     Revised Date:  2013-07-26    
Medline Journal Info:
Nlm Unique ID:  101150042     Medline TA:  Mol Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  426-34     Citation Subset:  IM    
Affiliation:
Department of Radiation Oncology, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA 90095-1714, USA.
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MeSH Terms
Descriptor/Qualifier:
Brain Neoplasms / genetics
Cell Line, Tumor
DNA Primers
Flow Cytometry
Gene Expression Regulation, Neoplastic* / radiation effects
Glioblastoma / genetics
Humans
Microscopy, Confocal
Proteasome Endopeptidase Complex / radiation effects
Proteasome Inhibitors*
Receptor, Epidermal Growth Factor / genetics*
Recombinant Fusion Proteins / biosynthesis
Retroviridae
Reverse Transcriptase Polymerase Chain Reaction
Grant Support
ID/Acronym/Agency:
CA-87887/CA/NCI NIH HHS; R01 CA101752/CA/NCI NIH HHS; R01 CA101752-04/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA Primers; 0/Proteasome Inhibitors; 0/Recombinant Fusion Proteins; 0/epidermal growth factor receptor VIII; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 3.4.99.-/ATP dependent 26S protease
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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