Erythropoietin can promote erythroid progenitor survival by repressing apoptosis through Bcl-XL and Bcl-2

Abstract

Erythropoietin (Epo), the hormone that is the principal regulator of red blood cell production, interacts with high-affinity receptors on the surface of erythroid progenitor cells and maintains their survival. Epo has been shown to promote cell viability by repressing apoptosis; however, the molecular mechanism involved is unclear. In the present studies we have examined whether Epo acts as a survival factor through the regulation of the bcl-2 family of apoptosis-regulatory genes. We addressed this issue in HCD-57, a murine erythroid progenitor cell line that requires Epo for proliferation and survival. When HCD-57 cells were cultured in the absence of Epo, Bcl-2 and Bcl-XL but not Bax were downregulated, and the cells underwent apoptotic cell death. HCD-57 cells infected with a retroviral vector encoding human Bcl-XL or Bcl-2 rapidly stopped proliferating but remained viable in the absence of Epo. Furthermore, endogenous levels of bcl-2 and bcl-XL were downregulated after Epo withdrawal in HCD-57 cells that remained viable through ectopic expression of human Bcl-XL, further indicating that Epo specifically maintains the expression of bcl-2 and bcl-XL. We also show that HCD-57 rescued from apoptosis by ectopic expression of Bcl-XL can undergo erythroid differentiation in the absence of Epo, demonstrating that a survival signal but not Epo itself is necessary for erythroid differentiation of HCD-57 progenitor cells. Thus, we propose a model whereby Epo functions as a survival factor by repressing apoptosis through Bcl-XL and Bcl-2 during proliferation and differentiation of erythroid progenitors.

A GATA‐specific inhibitor (K‐7174) rescues anemia induced by IL‐1β, TNF‐α, or l ‐NMMA

“…They reported that blocking the activity of TNF-α with a specific chimeric human/mouse monoclonal antibody improves the ACD seen in patients with RA and the beneficial effect of the treatment is mediated by down-regulating the TNF-α-induced apoptotic mechanisms in bone marrow (45). However, deprivation of Epo induces apoptosis of immature erythroid colony-forming cells through down-regulation of the Bcl-X (L) anti-apoptotic protein (46). Thus ACD is not only caused by increased TNF-α but also by IL-1β.…”

Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury

“…Several mechanisms have been proposed to explain the antiapoptotic effect of Epo both in hematopoiesis and neurons. Silva et al (59) studied a human erythroid progenitor cell line and showed that apoptosis was repressed by Epo via up-regulation of the Bcl-X L gene, an antiapoptotic gene of the Bcl-2 family. This concept is supported by the finding that Bcl-X L knockout mice exhibit severe anemia during embryogenesis (60).…”

Erythroid expansion and survival in response to acute anemia stress: The role of EPO receptor, GATA‐1, Bcl‐xL and caspase‐3

“…In addition to activating a program of erythroid gene expression (Welch et al, 2004), GATA-1 serves an antiapoptotic function by regulating the expression of Bcl-x L in erythroid cells, and cooperates with EPO signalling pathways to promote erythroid cell survival (Silva et al, 1999;Gregoli and Boundurant, 1997;Gregory et al, 1999). Furthermore, EPOdependent activation of the factor STAT5 is also involved in the induction of Bcl-x L expression (Silva et al, 1999;Socolovsky et al, 1999).…”