Regulation of Bcl-xL and Bim expression in erythropoiesis. (A) Model depicting expression of Bcl-xL (red) and Bim (blue) in the late and early erythroblast compartments, in basal erythropoiesis (solid lines) and during stress (fading shaded area). GATA-1 induces Bcl-xL and suppresses Bim during erythroid differentiation, with maximal responses achieved in late erythroblasts. The effects of EpoR during stress are superimposed on the basal pattern generated by GATA-1. EpoR signaling operates principally in the early erythroblast compartment, accelerating both Bim suppression and Bcl-xL induction. (B) Contrasting dynamic stress responses of the Bcl-xL, Bim and Fas pathways, all driven by the EpoR in the early erythroblast compartment. A sudden increase in stress drives a rapid, but transient, adapting Bcl-xL response. This response is reactivated with a further change in the stress level, but is insensitive to the absolute level of stress. Bim and Fas suppression in response to stress are slower but persistent and reflects the level of stress. (C) Mechanism of adaptation in the Bcl-xL response. In wild-type mice, p-Stat5 activates the transcription of negative regulators of Jak2 and Stat5 such as SOCS3, SOCS2, and CIS, which bind the EpoR distal cytoplasmic domain, limiting the duration of both the p-Stat5 and the Bcl-xL responses. In EpoR-H mice, absence of the distal EpoR domain results in a prolonged response and loss of adaptation. In EpoR-HM mice, both p-Stat5 activation and induction Bcl-xL are drastically attenuated because of the absence of Stat5 phosphotyrosine docking sites on the EpoR-HM mutant receptor.
