Detection of functional single-nucleotide polymorphisms that affect apoptosis.
Human EBV-transformed B lymphocyte cell lines (LCLs) were used to measure the apoptotic response of individuals to gamma radiation. The responses form a normal distribution around a median of 35.5% apoptosis with a range of 12-58%. This heterogeneous response has a genetic basis. LCLs from Caucasian donors and African American donors form distinct distributions of apoptotic response; all of the 11 LCLs comprising the lowest responding group (exhibiting between 12-20% apoptosis) are from Caucasian donors. The assay is capable of detecting significant effects of SNPs in two genes, MDM2 and AKT1, whose products are involved in controlling the p53 pathway and cellular response to DNA damage, suggesting that these data and this assay can be used to identify novel SNPs in other genes whose products impact the cellular response to radiation. Finally, the LCLs in the lowest apoptotic response group have the highest concentration of AKT1 protein and all harbor a haplotype in AKT1 that is present in Caucasians but absent in African Americans.
Harris
Sandra L
SL
Cancer Institute of New Jersey, Robert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
Gil
German
G
Robins
Harlan
H
Hu
Wenwei
W
Hirshfield
Kim
K
Bond
Elisabeth
E
Bond
Gareth
G
Levine
Arnold J
AJ
D017209:Apoptosis; D001402:B-Lymphocytes / Q000378:metabolism / Q000528:radiation effects; D002461:Cell Line, Transformed; D006239:Haplotypes; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology
D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt