Cytokine receptor common beta chain as a potential activator of cytokine withdrawal-induced apoptosis

Growth factors and cytokines play an important role in supporting cellular viability of various tissues during development due to their ability to sup press the default cell death program in each cell type. To date, neither th e triggering molecule nor the transduction pathway of these default apoptos is programs is understood. In this study, we explored the possibility that cytokine receptors are involved in modulating cytokine withdrawal-induced a poptosis (CWIA) in hematopoietic cells. Expression of the exogenous cytokin e receptor common beta chain (beta c), but not the alpha chains, accelerate d CWIA in multiple cytokine-dependent cell lines. Reduction of the expressi on level of endogenous beta c by antisense transcripts resulted in prolonge d survival during cytokine deprivation, suggesting a critical role of beta c in modulating CWIA. Fine mapping of the beta c subunit revealed that a me mbrane-proximal cytoplasmic sequence, designated the death enhancement regi on (DER), was critical to the death acceleration effect of beta c. Furtherm ore, DER accelerated cell death either as a chimeric membrane protein or as a cytosolic protein, suggesting that DER functions independently of the cy tokine receptor and membrane anchorage. Cross-linking of the chimeric membr ane-bound DER molecules by antibody or of the FK506-binding protein-DER fus ion protein by a synthetic dimerizing agent, AP1510, did not abrogate the d eath acceleration effect. Transient transfection assays further indicated t hat DER promoted cell death in the absence of serum in the nonhematopoietic 293 cell line. In summary, our data suggest that beta c plays an important role in modulating CWIA via an anchorage-independent and aggregation-insen sitive mechanism. These findings may facilitate further studies on the sign aling pathways of CWIA.