Details

Autor(en) / Beteiligte

• Gate, Laurent
• Majumdar, Rajrupa S.
• Lunk, Alexandra
• Tew, Kenneth D.

Titel

Increased Myeloproliferation in Glutathione S-Transferase π-deficient Mice Is Associated with a Deregulation of JNK and Janus Kinase/STAT Pathways

Ist Teil von

• The Journal of biological chemistry, 2004-03, Vol.279 (10), p.8608-8616

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2004

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• It has been shown that glutathione S-transferase π (GSTπ) interacts with and suppresses the activity of c-Jun NH2-terminal kinase (JNK). GST-deficient mice (GSTπ–/–) 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 GSTπ–/– animals but no change in T lymphocytes or natural killer cells. A peptidomimetic inhibitor of GSTπ that disrupts the interaction between GSTπ and JNK mimics in wild type mice the increased myeloproliferation observed in GSTπ–/– animals. Until now, the molecular basis for this effect has not been defined. In an in vitro hematopoiesis assay, interleukin-3, granulocyte colony-stimulating factor, and granulocyte/macrophage colony-stimulating factor were more effective at stimulating proliferation of hematopoietic cells in GSTπ–/– 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 GSTπ–/– animals. A more sustained phosphorylation of the STAT family of proteins was also observed in GSTπ–/– 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 GSTπ-deficient mice provides a viable mechanism for the increased myeloproliferation in these animals. These data also confirm the important role that GSTπ plays in the regulation of cell signaling pathways in a myeloproliferative setting.