Molecular genetic analysis of the calcineurin signaling pathways.

Calcineurin is a Ca2+- and calmodulin-regulated protein phosphatase that is important in Ca2+-mediated signal transduction. Recent application of the powerful techniques of molecular genetics has demonstrated that calcineurin is involved in the regulation of critical biological processes such as T cell activation, muscle hypertrophy, memory development, glucan synthesis, ion homeostasis, and cell cycle control. Notably, specific transcription factors have been shown to play a key role in regulating these functions, and their calcineurin-mediated dephosphorylation and nuclear translocation appear to be a central event in the signal transduction pathways. This review focuses on recent progress in these areas and discusses the evidence for cross-talk between calcineurin and other signaling pathways.

Tol1, a fission yeast phosphomonoesterase, is an in vivo target of lithium, and its deletion leads to sulfite auxotrophy.

Lithium is the drug of choice for the treatment of bipolar affective disorder. The identification of an in vivo target of lithium in fission yeast as a model organism may help in the understanding of lithium therapy. For this purpose, we have isolated genes whose overexpression improved cell growth under high LiCl concentrations. Overexpression of tol1(+), one of the isolated genes, increased the tolerance of wild-type yeast cells for LiCl but not for NaCl. tol1(+) encodes a member of the lithium-sensitive phosphomonoesterase protein family, and it exerts dual enzymatic activities, 3'(2'),5'-bisphosphate nucleotidase and inositol polyphosphate 1-phosphatase. tol1(+) gene-disrupted cells required high concentrations of sulfite in the medium for growth. Consistently, sulfite repressed the sulfate assimilation pathway in fission yeast. However, tol1(+) gene-disrupted cells could not fully recover from their growth defect and abnormal morphology even when the medium was supplemented with sulfite, suggesting the possible implication of inositol polyphosphate 1-phosphatase activity for cell growth and morphology. Given the remarkable functional conservation of the lithium-sensitive dual-specificity phosphomonoesterase between fission yeast and higher-eukaryotic cells during evolution, it may represent a likely in vivo target of lithium action across many species.