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Series GSE37464 Query DataSets for GSE37464
Status Public on Sep 01, 2013
Title Pleiotropic Effects of the Trichloroethylene-Associated P81S VHL Mutation on Metabolism, Apoptosis and ATM-Mediated DNA Damage Response
Organism Mus musculus
Experiment type Expression profiling by array
Summary Gene expression data from VHL teratomas comparing genes differentially expressed based on apoptotic response to tumor microenvironment.

Abstract
BACKGROUND:
The risk relevance of the P81S von Hippel-Lindau (VHL) gene hotspot mutation identified in clear cell renal cell carcinoma from individuals exposed occupationally to trichloroethylene (TCE) is not known. VHL mutations in hereditary VHL syndrome strongly correlate with phenotypic associations, but specific sporadic mutations in VHL that uniquely alter its protein function may provide a selective growth advantage for somatic cells harboring these mutations.
METHODS:
VHL deficient (Vhl -/- ) mouse embryonic stem cells were generated that stably express wild-type, P81S, or R167Q human VHL protein. Under hypoxic conditions, cell lines were examined for hypoxia-inducible transcription factor family (HIF) stabilization and E3-ubiquitin ligase complex interactions. In vivo, teratomas were examined for tumor size, proliferation, apoptosis, and immunohistochemistry and subjected to gene expression analysis. Wild-type, R167Q, and P81S VHL-expressing teratomas were also exposed to 5 Gy ionizing radiation to quantify apoptotic response. Proliferation and apoptosis and teratoma growth were analyzed by either Student t test or analysis of variance with Bonferroni correction. All statistical tests were two-sided.
RESULTS:
The P81S VHL mutation produces deregulation of HIF factors in cell culture but exhibits a growth advantage in the tumor microenvironment, in part because of suppression of apoptosis (P81S mean = 0.9%, 95% confidence interval = 0.6 to 1.2%; WT mean = 7.6%; 95% confidence interval = 6.4 to 8.8%; P < .001) coupled with sustained proliferation. Transcriptional analysis of P81S teratomas revealed the induction of metabolic pathways, antiapoptotic genes, and global suppression of key DNA damage response genes not observed in VHL wild-type or R167Q mutants. In vivo irradiation exposure showed that P81S mutant is resistant to ionizing radiation-induced apoptosis.
CONCLUSIONS:
The TCE-associated P81S VHL mutation can initiate a unique adaptive response required for selective tumor growth through pleiotropic effects on metabolic diversification, apoptosis suppression, and alteration of the DNA damage response.
 
Overall design Three genotypes of VHL teratomas were examined: Three replicate wildtype VHL, Three replicate R167Q VHL, and Four replicate P81S VHL (representing two replicates of two different P81S clones)
 
Contributor(s) DeSimone MC, Rathmell WK, Threadgill DW
Citation(s) 23990666
Submission date Apr 20, 2012
Last update date Apr 18, 2017
Contact name Michelle C DeSimone
E-mail(s) michelle.desimone@gmail.com
Organization name NCSU
Department Genetics
Lab Threadgill
Street address 112 Derieux Place
City Raleigh
State/province NC
ZIP/Postal code 27695
Country USA
 
Platforms (1)
GPL11533 [MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version]
Samples (10)
GSM920545 Teratoma, mouse embryonic stem cells electroporated with P81S VHL cDNA, biological rep 1
GSM920546 Teratoma, mouse embryonic stem cells electroporated with P81S VHL cDNA, biological rep 2
GSM920547 Teratoma, mouse embryonic stem cells electroporated with P81S VHL cDNA, biological rep 3
Relations
BioProject PRJNA160161

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Supplementary file Size Download File type/resource
GSE37464_RAW.tar 48.9 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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