GATA-1 and Erythropoietin Cooperate to Promote Erythroid Cell Survival by Regulating bcl-xL Expression

Gregory, T. Crimmins; Yu, Channing; Ma, Averil; Orkin, Stuart H.; Blobel, Gerd A.; Weiss, Mitchell J.

doi:10.1182/blood.v94.1.87.413k41_87_96

Cited by 339 publications

(156 citation statements)

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“…Thus, expressions of these proteins are involved in cell survival and proliferation of bone marrow progenitor cells with erythroid differentiation potential during the stress response. The striking positive correlation observed among EPO-R, GATA-1, and Bcl-x L are in agreement with a previous report (Gregory et al, 1999): this suggests that a particular intrinsic recovery program is suitable in bone marrow erythroid cells.…”

Section: Discussionsupporting

confidence: 93%

“…EPO-EPO-R signaling results in the survival, proliferation, and differentiation of erythroid progenitors (Jelkmann, 2004). Like EPO and EPO-R, GATA-1 serves an antiapoptotic function by regulating the expression of Bcl-x L required for erythroid cell survival (Gregory et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

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

Aispuru

Aguirre

Aquino-Esperanza

et al. 2008

Cell Biology International

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Erythropoietic stress occurs under conditions of tissular hypoxia, such as anemia. Functional relationships between erythroid bone marrow (BM) proliferation, differentiation, the expression of survival and apoptotic related proteins, as well as the features of the BM microenvironment upon acute anemic stress, are not fully elucidated. To achieve this aim, CF-1 Swiss mice were injected with a single dose of 5-fluorouracil (5-FU, 150 mg/kg ip) and a multiparametric analysis was conducted for 20 days. Apoptosis (TUNEL assay), BM architecture organization (scanning electronic microscopy), proliferation (DNA assay), differentiation (clonogenic cultures), expression of survival erythroid related proteins (EPO-R, GATA-1, Bcl-xL) as well as the expression of apoptotic- related proteins (Bax, activated Caspase-3) by Western blotting, were evaluated. Experimental data showed that apoptosis, arrest of cell proliferation and disruptions of BM architecture were maximal within the first period of acute stress (1-3 days). Bax and caspase-3 overexpressions were also coincident during this acute period. Moreover, from day 5 upon drug challenge BM responds to acute stress through the EPO-EPO-R system, prompting expressions of GATA-1 and Bcl-xL. Erythroid proliferation rates and red-cell-committed progenitors enhanced in a coordinated way to restore the size and function of the red cell compartment. A second overexpression wave of active caspase-3 was noticed during stress recovery. Together, these results indicate that in response to acute stress a dramatic increase in CFU-E (erythroid colony forming units) population is concomitant with upregulation of EPO-R, GATA-1 and Bcl-xL in the BM erythroid compartment, and that these concurrent processes are crucial for acquiring proper erythroid cell functionality without delayed response to tissular hypoxia.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Aispuru

Aguirre

Aquino-Esperanza

et al. 2008

Cell Biology International

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“…In this study, we identified an association between aberrant methylation of the 5¢cis-regulatory region of GATA1 with a failure to up-regulate its gene expression during erythropoiesis in MDS lower and higher risk patients. GATA1 is critical for erythroid differentiation and could be called 'erythroid master gene' (7,22,(70)(71)(72). A previous study already associated dysregulated GATA1 expression with an arrest in primitive erythroid cell development (73) and with an erythroid maturation block in low-risk MDS (6).…”

Section: Discussionmentioning

confidence: 99%

Epigenetic dysregulation of GATA1 is involved in myelodysplastic syndromes dyserythropoiesis

Hopfer¹,

Nolte²,

Mossner³

et al. 2011

European J of Haematology

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Myelodysplastic syndromes (MDS) are characterized by dyserythropoiesis resulting in anemia. This pathological hallmark is incompletely understood. Notch signaling has been linked to impaired erythropoietic and megakaryopoietic development of CD34+ progenitor cells, but its role in MDS is unclear. We have analyzed the transcriptional activity of Notch pathway elements and its association with the key erythroid factor globin transcription factor 1 (GATA1) and the apoptosis regulatory gene B-cell lymphoma-xl (BCLxl) in MDS. The methylation of GATA1 erythroid promoter CpG dinucleotides flanking cis-regulatory elements, including an N-box suppressor binding site for HES1 and a GATA-box binding site, was examined in normal and MDS erythropoiesis. We have generated a kinetic in vitro model of MDS erythropoiesis using CD34+ bone marrow cells from healthy donors (n = 7) and patients with MDS (low risk: RA/n = 6, RARS/n = 3; high risk: RAEB/n = 4, RAEB-T/n = 2). RNA expression of GATA1, BCLxl, DLK1, Notch1, HES1, and HERP2 was measured by real-time RT-PCR (qPCR). DNA methylation at seven CpG dinucleotides of the GATA1 gene promoter was quantitatively analyzed by pyrosequencing of bisulfite-treated genomic DNA at any specific time point. For the Notch pathway elements, no conclusive expression differences were found between MDS and normal erythropoiesis. But we found steadily up-regulated RNA expression of GATA1 and of BCLxl during late normal erythropoietic differentiation. In contrast, during MDS, erythropoiesis a loss of typical up-regulation of GATA1 and BCLxl was observed. Hypermethylation of CpG dinucleotides flanking the repressor HES1 binding site within the 5' region of GATA1 was detected particularly during late MDS erythropoiesis. Interestingly, decremental GATA1 promotor methylation values were seen during normal erythropoiesis matching GATA1 RNA up-regulation. Our data show that the critical erythropoietic transcription factor GATA1 as well as the antiapoptotic molecule BCLxl fails to be normally up-regulated during MDS erythropoiesis. The higher residual 5'-GATA1 methylation values in MDS erythropoiesis but decremental loss thereof in normal erythropoiesis suggest a gene dose effect for GATA1 during erythropoiesis being finely tuned by CpG methylation. Its dysregulation may contribute to the ineffective erythropoiesis observed in MDS.

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“…Bcl-XL acts by preventing the release of pro-apoptotic molecules from mitochondria (Gregoli and Bondurant, 1999). The transcription factor GATA-1 is involved in Epo-mediated up-regulation of Bcl-XL (Gregory et al, 1999) and positively regulates expression of erythroid genes (Pevny et al, 1991). This transcription factor is a target for caspases in cells undergoing death upon Epo starvation or induction of death receptor Fas (De Maria et al, 1999;Gregoli and Bondurant, 1999), but it remains uncleaved during cell differentiation stimulated with Epo (Zermati et al, 2001;Carlile et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

A non‐apoptotic function of caspase‐3 in pharmacologically‐induced differentiation of K562 cells

Sztiller-Sikorska¹,

Jakubowska²,

Wozniak³

et al. 2009

British J Pharmacology

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Background and purpose: Several anticancer drugs with diverse chemical structures can induce differentiation of cancer cells. This study was undertaken to explore the potential contribution of caspase-3 to pharmacologically-induced differentiation of K562 cells. Experimental approach:We assessed differentiation by measuring the expression of glycophorin A and haemoglobin synthesis in K562 cells treated with low concentrations of doxorubicin, hydroxyurea, cytosine arabinoside, cisplatin and haemin. Caspase-3 activation, mitochondrial membrane potential dissipation and viability were assessed by FACS. GATA-1-binding activity was evaluated by EMSA. Key results: Treatment of K562 cells with low concentrations of the tested drugs activated caspase-3 but did not trigger detectable apoptosis. Instead, elevated levels of haemoglobin-positive and glycophorin A/caspase-3-double-positive cells were observed, suggesting involvement of caspase-3 in drug-induced differentiation. Inhibition of caspase-3 activity significantly reduced the ability of K562 cells to execute the differentiation programme. Mitochondrial membrane potential dissipation was observed, indicating involvement of the mitochondrial pathway. Binding activity of GATA-1, transcription factor responsible for differentiation and cell survival, was not diminished by increased caspase-3 activity during drug-stimulated differentiation. Conclusions and implications:Our results could explain how anticancer drugs, with diverse structures and modes of action, can stimulate erythroid differentiation in leukaemic cells with appropriate genetic backgrounds. Our findings imply that some similarities exist between pharmacologically-induced differentiation of erythroleukaemic cells and normal erythropoiesis, both involving caspase-3 activation at high levels of anti-apoptotic protein Bcl-X L and chaperone protein Hsp70 (heat shock protein 70). Therefore, the functions of caspase-3, unrelated to cell death, can be extended to pharmacologically-induced differentiation of some cancer cells.

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GATA-1 and Erythropoietin Cooperate to Promote Erythroid Cell Survival by Regulating bcl-xL Expression

Cited by 339 publications

References 54 publications

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

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

Epigenetic dysregulation of GATA1 is involved in myelodysplastic syndromes dyserythropoiesis

A non‐apoptotic function of caspase‐3 in pharmacologically‐induced differentiation of K562 cells

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GATA-1 and Erythropoietin Cooperate to Promote Erythroid Cell Survival by Regulating bcl-xL Expression

Cited by 339 publications

References 54 publications

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

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

Epigenetic dysregulation of GATA1 is involved in myelodysplastic syndromes dyserythropoiesis

A non‐apoptotic function of caspase‐3 in pharmacologically‐induced differentiation of K562 cells

Contact Info

Product

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

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