Role of glutamine depletion in directing tissue-specific nutrient stress responses to L-asparaginase.

摘要: Abstract l-Asparaginase is important in the induction regimen for treating acute lymphoblastic leukemia. Cytotoxic complications are clinically significant problems lacking mechanistic insight. To reveal tissue-specific molecular responses to this drug, mice were administered asparaginase from either Escherichia coli (clinically used) or Wolinella succinogenes (novel, glutaminase-free form). Both enzymes abolished serum asparagine, but only E. form reduced circulating glutamine. protein synthesis liver and spleen not pancreas via increased phosphorylation of translation factor eIF2. In contrast, treatment with caused no untoward changes any tissue examined. Treating deleted eIF2 kinase, GCN2, enzyme showed be GCN2-dependent, initially. Furthermore, although was by asparaginase, expression amino acid stress response genes, asparagine synthetase CHOP/GADD153, as a result both enzymes, even tissues demonstrating change phosphorylation. Finally, signaling downstream mammalian target rapamycin kinase repressed asparaginase. These data demonstrate that nutrient exacerbated glutamine depletion. Importantly, CHOP does require phosphorylation, signifying alternate auxiliary means inducing gene under conditions depletion whole animal.