It has been shown that glutathione S-transferase (GST) interacts with and suppresses the activity of c-Jun NH 2 -terminal kinase (JNK). GST-deficient mice (GST ؊/؊ ) have higher levels of circulating white blood cells, with similar proportions of lymphocytes, monocytes, and granulocytes. Interestingly, a selective expansion of splenic B lymphocytes was observed in GST ؊/؊ animals but no change in T lymphocytes or natural killer cells. A peptidomimetic inhibitor of GST that disrupts the interaction between GST and JNK mimics in wild type mice the increased myeloproliferation observed in GST ؊/؊ animals. Until now, the molecular basis for this effect has not been defined. In an in vitro hematopoiesis assay, interleukin-3, granulocyte colonystimulating factor, and granulocyte/macrophage colonystimulating factor were more effective at stimulating proliferation of hematopoietic cells in GST ؊/؊ mice than in wild type. The JNK inhibitor SP600125 which caused little inhibition of cytokine-induced myeloproliferation in wild type mice, decreased the number of colonies in GST ؊/؊ animals. A more sustained phosphorylation of the STAT family of proteins was also observed in GST ؊/؊ bone marrow-derived mast cells exposed to interleukin-3. This was associated with an increased proliferation and a down-regulation of expression of negative regulators of the Janus kinase-STAT pathway SHP, Src homology 2 domain-containing tyrosine phosphatase-1 and -2. The increased activation of JNK and STATs in GST-deficient mice provides a viable mechanism for the increased myeloproliferation in these animals. These data also confirm the important role that GST plays in the regulation of cell signaling pathways in a myeloproliferative setting.

The role of glutathione S-transferase (GST) in tumor development has been previously suggested; however the exact function of this enzyme in carcinogenesis remains unclear. GST has been identified as a modulator of cell signaling by interacting with and inhibiting c-Jun N-terminal kinase (JNK). This kinase has been in turn described as a regulator of p53 stability and transcriptional activity. To study the possible interaction between GST and p53, we crossed GST-deficient animals with p53 ؊/؊ mice. Double knock out animals were viable but developed tumors within 6 months of age; the life span of these animals was however similar to that of GST Glutathione S-transferases (GST) are ubiquitously expressed in plants and animals and have diverse roles in the conjugation of glutathione to electrophilic species. In mammals, 6 different isoforms ␣, , , , and have been identified. 1 GST overexpression has been observed in many tumors as compared to the surrounding normal tissues and in various cancer cell lines resistant to anticancer agents. 2 However, the precise role that this enzyme plays in resistance to anticancer drugs remains ill-defined, particularly since GST transfection does not always confer resistance to chemotherapeutic agents. 3 More recently, it has been shown that GST acts as a regulator of mitogen-activated protein (MAP) kinases. GST is an endogenous inhibitor of c-Jun NH 2 -terminal kinase (JNK), mediated by interactions with the N-terminal region of the kinase. 4,5 Following oxidative stress, it has been hypothesized that GST oligomerizes and disassociates from JNK, which then becomes phosphorylated. 4 GST can also modulate the activation of p38 and extracellular-regulated kinase (ERK). For example, in NIH 3T3 cells, the forced expression of GST inhibits JNK activity and activates ERK and p38 kinase. 6 In addition, in GST deficient mouse embryo fibroblasts, basal activities of JNK and ERK are higher than in their wild-type counterparts. 4,7 GST expression has been shown to play a role in chemically induced tumorigenesis. GST-deficient mice had a higher incidence of skin tumors following treatment by 7,12-dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (PMA) than their wild-type counterparts. 8 These observations could be correlated with the function of GST in the metabolism of polycyclic aromatic hydrocarbons. 9 It is also well established that GST is overexpressed with high frequency in a wide variety of tumors including breast, colon, oesophagus, kidney and lung, while its level in normal surrounding tissues is relatively low. 3 In contrast, GST expression is lost in other cancer types including prostatic and hepatocellular carcinomas, a process associated with hypermethylation of the enzyme's promoter. 10 However, the involvement of GST in the tumorigenesis process is still not well defined.Over the past decades, the carcinogenesis process has been extensively studied. It has been shown that the lack of expression, or the mutation, of tumor suppressor genes such as p53 repre...

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