Carcinogenesis Advance Access published online on June 8, 2007
Carcinogenesis, doi:10.1093/carcin/bgm135
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Differential effects of glutathione S-transferase pi (GSTP1) haplotypes on cell proliferation and apoptosis
1 Human Disease and Genomics Research Group, Institute of Science and Technology in Medicine, Keele University, University Hospital of North Staffordshire, Stoke-on-Trent, Staffordshire, ST4 7QB, UK
2 Department of Engineering Materials, Kroto Research Institute, Sheffield University, Sheffield, S3 7HQ, UK
3 Address correspondence to: Dr. Paul R Hoban, Human Disease and Genomics Research Group, Institute for Science and Technology in Medicine, Keele University School of Medicine, University Hospital of North Staffordshire, Stoke-on-Trent, ST4 7QB, UK. Tel. +44 1782 555226; Fax. +44 1782 717079; E-mail: p.r.hoban{at}keele.ac.uk
Expression of the glutathione S-transferase, GSTP1 is associated with phase 1 detoxification of the products of oxidative stress. Recently GSTP1 expression has been implicated in the regulation of cell proliferation and apoptosis through direct interaction with the c-Jun NH2 terminal kinase, (JNK). GSTP1 is polymorphic and allelic variants have been associated with disease susceptibility and clinical outcome. However, the influence of GSTP1 alleles on proliferation and apoptosis has not been previously studied. To investigate this, we have examined the effects of inducible expression of wild-type GSTP1*A and mutant GSTP1*C haplotypes on cell proliferation and apoptosis in NIH3T3 fibroblasts. Cells expressing GSTP1*A displayed increased doubling times and a delayed G1-S phase transition compared to cells expressing GSTP1*C. Both GSTP1*A and GSTP1*C haplotypes protected cells from undergoing apoptosis when exposed to oxidative stress. However, analysis of JNK status revealed that only GSTP1*C expression led to a reduction in JNK activity compared to GSTP1*A expressing cells and non-induced cells. We further examined the effect of GSTP1 alleles on colony forming efficiency in soft agar following exposure to oxidative stress and found that GSTP1*A expressing clones had increased colony forming efficiency compared to non-induced and GSTP1*C expressing clones. Our data suggest that GSTP1 alleles have differential effects on proliferation and apoptosis; GSTP1*A reduces cellular proliferation and protects against apoptosis through a JNK-independent mechanism. In contrast, GSTP1*C does not influence cellular proliferation but protects cells from apoptosis through JNK-mediated mechanisms.
Key Words: Glutathione S-transferase • polymorphism • cell proliferation • apoptosis
Received April 2, 2007; revised May 23, 2007; accepted May 23, 2007.
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