The Experts below are selected from a list of 7098 Experts worldwide ranked by ideXlab platform
Paola Turano - One of the best experts on this subject based on the ideXlab platform.
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The anti-apoptotic Bcl-X(L) Protein, a new piece in the puzzle of cytochrome c interactome.
PLoS ONE, 2011Co-Authors: Ivano Bertini, Soizic Chevance, Rebecca Del Conte, Daniela Lalli, Paola TuranoAbstract:A structural model of the adduct between human cytochrome c and the human anti-apoptotic Protein Bcl-X(L), which defines the Protein-Protein interaction surface, was obtained from solution NMR chemical shift perturbation data. The atomic level information reveals key intermolecular contacts identifying new potentially druggable areas on cytochrome c and Bcl-X(L). Involvement of residues on cytochrome c other than those in its compleXes with electron transfer partners is apparent. Key differences in the contact area also eXist between the Bcl-X(L) adduct with the Bak peptide and that with cytochrome c. The present model provides insights to the mechanism by which cytochrome c translocated to cytosol can be intercepted, so that the apoptosome is not assembled.
Helmut Dolznig - One of the best experts on this subject based on the ideXlab platform.
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erythroid progenitor renewal versus differentiation genetic evidence for cell autonomous essential functions of epor stat5 and the gr
Oncogene, 2006Co-Authors: Helmut Dolznig, Bianca Habermann, Eva Maria Deiner, Florian Grebien, K Stangl, Andrea Kolbus, Marc A Kerenyi, M Kieslinger, Richard MorigglAbstract:The balance between hematopoietic progenitor commitment and self-renewal versus differentiation is controlled by various transcriptional regulators cooperating with cytokine receptors. Disruption of this balance is increasingly recognized as important in the development of leukemia, by causing enhanced renewal and differentiation arrest. We studied regulation of renewal versus differentiation in primary murine erythroid progenitors that require cooperation of erythropoietin receptor (EpoR), the receptor tyrosine kinase c-Kit and a transcriptional regulator (glucocorticoid receptor; GR) for sustained renewal. However, mice defective for GR- (GR(dim/dim)), EpoR- (EpoR(H)) or STAT5ab function (Stat5ab(-/-)) show no severe erythropoiesis defects in vivo. Using primary erythroblast cultures from these mutants, we present genetic evidence that functional GR, EpoR, and Stat5 are essential for erythroblast renewal in vitro. Cells from GR(dim/dim), EpoR(H), and Stat5ab(-/-) mice showed enhanced differentiation instead of renewal, causing accumulation of mature cells and gradual proliferation arrest. Stat5ab was additionally required for Epo-induced terminal differentiation: differentiating Stat5ab(-/-) erythroblasts underwent apoptosis instead of erythrocyte maturation, due to absent induction of the antiapoptotic Protein Bcl-X(L). This defect could be fully rescued by eXogenous Bcl-X(L). These data suggest that signaling molecules driving leukemic proliferation may also be essential for prolonged self-renewal of normal erythroid progenitors.
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Apoptosis Protection by the Epo Target Bcl-XL Allows Factor-Independent Differentiation of Primary Erythroblasts
Current Biology, 2002Co-Authors: Helmut Dolznig, Bianca Habermann, Katharina Stangl, Eva Maria Deiner, Ernst W. MüllnerAbstract:Abstract Background: Erythropoietin (Epo) is required for correct eXecution of the erythroid differentiation program. Erythropoiesis requires Bcl-X L , a major late target of Epo-receptor signaling. Mice lacking Bcl-X L die around embryonic age E12.5, forming normal erythroid progenitors but lacking functional red cells. Recently, serum-free culture conditions for eXpansion of murine red cell progenitors were developed, yielding cells capable of in vivo-like terminal differentiation into enucleated erythrocytes, in response to Epo/insulin. Here we address whether Epo function during terminal maturation involves a cytokine-independent "default program," requiring only apoptosis inhibition through Epo-dependent upregulation of Bcl-X L . Results: EXogenous eXpression of Bcl-X L or Bcl-2 in primary murine erythroblasts or clonal erythroblast lines derived from p53 −/− mice allowed these cells to undergo terminal erythroid maturation, in the complete absence of cytokines. A potential autocrine Epo loop was ruled out by respective neutralizing antibodies. Importantly, sustained proliferation of Bcl-X L -eXpressing immature erythroblasts still required respective factors (Epo, stem cell factor [SCF], and the glucocorticoid receptor ligand deXamethasone [DeX]). Epo-independent differentiation in these Bcl-X L - or Bcl-2-eXpressing, primary erythroblasts was thus triggered by removal of the renewal factors SCF and DeX. This initiated the maturation-specific eXpression cascade of erythroid transcription factors, followed by differentiation divisions (characterized by a short G1 phase and decrease in cell size), hemoglobin accumulation, and enucleation. Conclusions: During erythroid maturation, Epo regulates red cell numbers via apoptosis inhibition, caused by Epo-dependent upregulation of the antiapoptotic Protein Bcl-X L . This allows "default" terminal differentiation of apoptosis-protected, committed erythroblasts, independent of any eXogenous signals.
Ann Zeuner - One of the best experts on this subject based on the ideXlab platform.
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hsp70 regulates erythropoiesis by preventing caspase 3 mediated cleavage of gata 1
Nature, 2007Co-Authors: Jeanantoine Ribeil, Yael Zermati, Julie Vandekerckhove, Severine Cathelin, Joelle Kersual, Michael Dussiot, Severine Coulon, Ivan C Moura, Ann ZeunerAbstract:Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors. The transcription factor GATA-1, which performs an essential function in erythroid differentiation by positively regulating promoters of erythroid and anti-apoptotic genes, is cleaved by caspases in erythroid precursors undergoing cell death upon erythropoietin starvation or engagement of the death receptor Fas. In contrast, by an unknown mechanism, GATA-1 remains uncleaved when these cells undergo terminal differentiation upon stimulation with Epo. Here we show that during differentiation, but not during apoptosis, the chaperone Protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear eXport of Hsp70 and the cleavage of GATA-1. In an in vitro assay, Hsp70 protects GATA-1 from caspase-3-mediated proteolysis through its peptide-binding domain. The use of RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin leads to GATA-1 cleavage, a decrease in haemoglobin content, downregulation of the eXpression of the anti-apoptotic Protein Bcl-X(L), and cell death by apoptosis. These effects are abrogated by the transduction of a caspase-resistant GATA-1 mutant. Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis.
Ernst W. Müllner - One of the best experts on this subject based on the ideXlab platform.
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Apoptosis Protection by the Epo Target Bcl-XL Allows Factor-Independent Differentiation of Primary Erythroblasts
Current Biology, 2002Co-Authors: Helmut Dolznig, Bianca Habermann, Katharina Stangl, Eva Maria Deiner, Ernst W. MüllnerAbstract:Abstract Background: Erythropoietin (Epo) is required for correct eXecution of the erythroid differentiation program. Erythropoiesis requires Bcl-X L , a major late target of Epo-receptor signaling. Mice lacking Bcl-X L die around embryonic age E12.5, forming normal erythroid progenitors but lacking functional red cells. Recently, serum-free culture conditions for eXpansion of murine red cell progenitors were developed, yielding cells capable of in vivo-like terminal differentiation into enucleated erythrocytes, in response to Epo/insulin. Here we address whether Epo function during terminal maturation involves a cytokine-independent "default program," requiring only apoptosis inhibition through Epo-dependent upregulation of Bcl-X L . Results: EXogenous eXpression of Bcl-X L or Bcl-2 in primary murine erythroblasts or clonal erythroblast lines derived from p53 −/− mice allowed these cells to undergo terminal erythroid maturation, in the complete absence of cytokines. A potential autocrine Epo loop was ruled out by respective neutralizing antibodies. Importantly, sustained proliferation of Bcl-X L -eXpressing immature erythroblasts still required respective factors (Epo, stem cell factor [SCF], and the glucocorticoid receptor ligand deXamethasone [DeX]). Epo-independent differentiation in these Bcl-X L - or Bcl-2-eXpressing, primary erythroblasts was thus triggered by removal of the renewal factors SCF and DeX. This initiated the maturation-specific eXpression cascade of erythroid transcription factors, followed by differentiation divisions (characterized by a short G1 phase and decrease in cell size), hemoglobin accumulation, and enucleation. Conclusions: During erythroid maturation, Epo regulates red cell numbers via apoptosis inhibition, caused by Epo-dependent upregulation of the antiapoptotic Protein Bcl-X L . This allows "default" terminal differentiation of apoptosis-protected, committed erythroblasts, independent of any eXogenous signals.
Yael Zermati - One of the best experts on this subject based on the ideXlab platform.
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hsp70 regulates erythropoiesis by preventing caspase 3 mediated cleavage of gata 1
Nature, 2007Co-Authors: Jeanantoine Ribeil, Yael Zermati, Julie Vandekerckhove, Severine Cathelin, Joelle Kersual, Michael Dussiot, Severine Coulon, Ivan C Moura, Ann ZeunerAbstract:Caspase-3 is activated during both terminal differentiation and erythropoietin-starvation-induced apoptosis of human erythroid precursors. The transcription factor GATA-1, which performs an essential function in erythroid differentiation by positively regulating promoters of erythroid and anti-apoptotic genes, is cleaved by caspases in erythroid precursors undergoing cell death upon erythropoietin starvation or engagement of the death receptor Fas. In contrast, by an unknown mechanism, GATA-1 remains uncleaved when these cells undergo terminal differentiation upon stimulation with Epo. Here we show that during differentiation, but not during apoptosis, the chaperone Protein Hsp70 protects GATA-1 from caspase-mediated proteolysis. At the onset of caspase activation, Hsp70 co-localizes and interacts with GATA-1 in the nucleus of erythroid precursors undergoing terminal differentiation. In contrast, erythropoietin starvation induces the nuclear eXport of Hsp70 and the cleavage of GATA-1. In an in vitro assay, Hsp70 protects GATA-1 from caspase-3-mediated proteolysis through its peptide-binding domain. The use of RNA-mediated interference to decrease the Hsp70 content of erythroid precursors cultured in the presence of erythropoietin leads to GATA-1 cleavage, a decrease in haemoglobin content, downregulation of the eXpression of the anti-apoptotic Protein Bcl-X(L), and cell death by apoptosis. These effects are abrogated by the transduction of a caspase-resistant GATA-1 mutant. Thus, in erythroid precursors undergoing terminal differentiation, Hsp70 prevents active caspase-3 from cleaving GATA-1 and inducing apoptosis.
