Apoptosis Protection by the Epo Target Bcl-XL Allows Factor-Independent Differentiation of Primary Erythroblasts

Dolznig, Helmut; Habermann, Bianca; Stangl, Katharina; Deiner, Eva Maria; Moriggl, Richard; Beug, Hartmut; Müllner, Ernst W.

doi:10.1016/s0960-9822(02)00930-2

Cited by 126 publications

(125 citation statements)

References 40 publications

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“…29 Signaling from EpoR through Jak2/Stat5 30,31 prevents apoptosis on this cell lineage from late erythroid progenitors (CFU-E) until the onset of hemoglobinization, 32,33 and one important target gene of this cascade is bcl-x. 34 Studies using bcl-x-null mice demonstrated a critical role for this gene at the end of erythroid maturation when maximal hemoglobin synthesis occurs. 35 RBPjk À/À erythroid cells show a clear upregulation of genes involved in this antiapoptotic pathway, such as EPO, EPO-R, bcl-x and bcl-2, suggesting that Notch may induce apoptosis by impinging on this pathway.…”

Section: Discussionmentioning

confidence: 99%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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Programmed cell death plays an important role in erythropoiesis under physiological and pathological conditions. In this study, we show that the Notch/RBPjj signaling pathway induces erythroid apoptosis in different hematopoietic tissues, including yolk sac and bone marrow as well as in murine erythroleukemia cells. In RBPjj À/À yolk sacs, erythroid cells have a decreased rate of cell death that results in increased number of Ter119 þ cells. A similar effect is observed when Notch activity is abrogated by incubation with the c-secretase inhibitors, DAPT or L685,458. We demonstrate that incubation with Jagged1-expressing cells has a proapoptotic effect in erythroid cells from adult bone marrow that is prevented by blocking Notch activity. Finally, we show that the sole expression of the activated Notch1 protein is sufficient to induce apoptosis in hexametilene-bisacetamide-differentiating murine erythroleukemia cells. Together these results demonstrate that Notch regulates erythroid homeostasis by inducing apoptosis.

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Section: Discussionmentioning

confidence: 99%

The notch pathway positively regulates programmed cell death during erythroid differentiation

et al. 2007

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“…34 Studies on an immortal line of phenotypically normal mouse erythroblasts provided further details about the antiapoptotic role of Bcl-X L in erythroid maturation. 35 These cells were maintained in an undifferentiated state by agents promoting selfrenewal, such as SCF and glucocorticoids, while they were induced to differentiate by Epo. Overexpression of the Bcl-X L gene allowed these cells to undergo terminal differentiation to mature erythrocytes in the absence of Epo.…”

Section: Figurementioning

confidence: 99%

“…Overexpression of the Bcl-X L gene allowed these cells to undergo terminal differentiation to mature erythrocytes in the absence of Epo. 35 The molecular basis responsible for the elevated expression of Bcl-X L in erythroid cells is unknown at the moment. The promoter of the Bcl-X L gene used for the start of the transcription in erythroid cells is localized at 5 0 in close proximity to the start initiation codon ATG.…”

Section: Figurementioning

confidence: 99%

Apoptotic mechanisms in the control of erythropoiesis

2004

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Erythropoiesis is a complex multistep process encompassing the differentiation of hemopoietic stem cells to mature erythrocytes. The steps involved in this complex differentiation process are numerous and involve first the differentiation to early erythoid progenitors (burst-forming units-erythroid, BFU-E), then to late erythroid progenitors (colony-forming unitserythroid) and finally to morphologically recognizable erythroid precursors. A key event of late stages of erythropoiesis is nuclear condensation, followed by extrusion of the nucleus to produce enucleated reticulocytes and finally mature erythrocytes. During the differentiation process, the cells became progressively sensitive to erythropoietin that controls both the survival and proliferation of erythroid cells.A normal homeostasis of the erythropoietic system requires an appropriate balance between the rate of erythroid cell production and red blood cell destruction. Growing evidences outlined in the present review indicate that apoptotic mechanism play a relevant role in the control of erythropoiesis under physiologic and pathologic conditions. Withdrawal of erythropoietin or stimulation of death receptors such as Fas or TRAIL-Rs leads to activation of a subset of caspases-3, -7 and -8, which then cleave the transcription factors GATA-1 and TAL-1 and trigger apoptosis. In addition, there is evidence that a number of caspases are physiologically activated during erythroid differentiation and are functionally required for erythroid maturation. Several caspase substrates are cleaved in differentiating cells, including the protein acinus whose activation by cleavage is required for chromatin condensation.The studies on normal erythropoiesis have clearly indicated that immature erythroid precursors are sensitive to apoptotic triggering mediated by activation of the intrinsic and extrinsic apoptotic pathways. These apoptotic mechanisms are frequently exacerbated in some pathologic conditions, associated with the development of anemia (ie, thalassemias, multiple myeloma, myelodysplasia, aplastic anemia).The considerable progress in our understanding of the apoptotic mechanisms underlying normal and pathologic erythropoiesis may offer the way to improve the treatment of several pathologic conditions associated with the development of anemia.

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“…In the past several years in vitro culture systems have been developed that faithfully recapitulate red blood cell development in vitro employing various types of hematopoietic progenitor cells and culture conditions (Fibach et al, 1991;Dolznig et al, 1995Dolznig et al, , 2001Dolznig et al, , 2002Wessely et al, 1997;Bartunek and Zenke, 1998;Panzenbock et al, 1998;von Lindern et al, 1999;Zhang et al, 2001;Bartunek et al, 2002). Such in vitro differentiation systems have allowed the study of the molecular mechanisms that underlie the erythroid cell differentiation program.…”

Section: Introductionmentioning

confidence: 99%

GATA-1 and c-myb crosstalk during red blood cell differentiation through GATA-1 binding sites in the c-myb promoter

et al. 2003

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Apoptosis Protection by the Epo Target Bcl-XL Allows Factor-Independent Differentiation of Primary Erythroblasts

Cited by 126 publications

References 40 publications

The notch pathway positively regulates programmed cell death during erythroid differentiation

The notch pathway positively regulates programmed cell death during erythroid differentiation

Apoptotic mechanisms in the control of erythropoiesis

GATA-1 and c-myb crosstalk during red blood cell differentiation through GATA-1 binding sites in the c-myb promoter

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