Cytokine-mediated cell survival.

Pathways through which signals emanating from cytokine receptors support cell survival have long been a focus of intensive research. For Baf-3, a murine interleukin 3-dependent cell line, the 2 distinct pathways involved are JAK/STATs/Bcl-xL and Ras/PI3-K. The latter is indispensable for long-term cell survival through down-regulation of Bim, a BH3-only cell death activator of the Bcl-2 superfamily. Thus, Bim is likely to be a key factor for cytokine-initiated regulation of cell survival in both hematopoietic cells and neuronal cells. Cytokines (like neurotrophic factors) regulate Bim expression at at least 3 levels: (1) at the messenger RNA (mRNA) level through transcriptional regulation and possibly through mRNA stability, (2) at the protein level through proteasome-dependent regulation of protein degradation, and (3) by affecting subcellular localization through regulation of the potential to bind to the dynein motor complex. Bim function may be regulated in different ways in certain situations such that the relative importance of these 3 mechanisms may differ among cell types. For hematopoiesis, mRNA regulation seems to be the most important. Bim is also implicated in leukemogenesis caused by the Bcr-Abl chimeric tyrosine kinase and constitutively active mutants of receptor tyrosine kinases.