Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway

Zhao, Wei; Kitidis, Claire; Fleming, Mark D.; Lodish, Harvey F.; Ghaffari, Saghi

doi:10.1182/blood-2005-06-2516

Cited by 172 publications

(161 citation statements)

References 72 publications

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“…In erythroid cells exposed to erythropoietin, GATA-1 is the final effector of signalling pathways involving phosphatidylinositol-3-phosphate/protein kinase, B-Akt (Zhao et al, 2006), which phosphorylates the transcription factor on serine 310 (Kadri et al, 2005), and mitogen-activated protein kinase (MAPK) cascade, which phosphorylates GATA-1 on serine 26 and 178 (Towatari et al, 2004;Yu et al, 2005). Interestingly, the anti-apoptotic function of GATA-1 has been found to be strongly dependent upon its phosphorylation at the serine 26 position (Yu et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

et al. 2010

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Expression of survivin, a member of the inhibitor of apoptosis protein family, is elevated in human cancers and considered as a new therapeutic target. Mechanism upregulating survivin expression in tumour cells is poorly understood. In this study, we show that breast cancer patients harbouring a polymorphism G235A in the survivin promoter present a higher level of survivin expression. This polymorphism creates a binding site for the transcription factor GATA-1 inducing a second GATA-1-binding site in survivin promoter. At the mRNA level, GATA-1 was present in breast carcinomas and adjacent normal tissues, whereas the protein was only detected in carcinomas by western blot and immunohistochemistry. Transfection of wild-type and different constitutively active GATA-1 mutants (serine 26, 178 or 310) showed that only phospho-serine 26 GATA-1 was able to increase survivin expression. This increase was higher in G235A than in G235G cell lines. Phospho-serine 26 GATA-1 bound directly survivin promoter, with a stronger interaction in G235A than in G235G polymorphism indicating that both GATA-1-binding sites are functional. These data identify GATA-1 as a key feature in tumour aggressiveness by enhancing survivin expression and delineate its targeting as a possible new therapeutic strategy in breast carcinomas.

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Section: Discussionmentioning

confidence: 99%

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

et al. 2010

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“…The binding of EPO to EpoR results in the phosphorylation and activation of Jak2, which is followed by the activation of phosphatidylinositol-3 kinase (PI-3K) and protein kinase B (Akt) signal transduction proteins. 6,34,40,41 Activated Akt suppresses both the degradation of genomic DNA and the externalization of phosphatidylserine, events essential for apoptosis. Furthermore, EPO may also inhibit apoptosis through the upregulation of the Bcl-2 family proteins.…”

Section: Discussionmentioning

confidence: 99%

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Sigounas

Salleng

Mehlhop

et al. 2008

Intl Journal of Cancer

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Organ toxicity induced by chemotherapeutic drugs is a serious obstacle in the effective treatment of patients suffering from cancer and autoimmune disease. A strong association exists between pulmonary toxicity, particularly fibrosis, and chemotherapeutic drugs. Attempts have been made to identify compounds capable of suppressing fibrosis. In addition to its erythropoietic activity, erythropoietin (EPO) has been shown to have effects on nonhemopoietic cells. Therefore, we postulated that EPO may exert beneficial effects on lung tissue during chemotherapy. To test our hypothesis, we investigated pulmonary changes caused by bleomycin, a fibrosis‐inducing agent, in animals treated with the drug alone and in combination with EPO. Fibrosis, cellular alterations and structural changes were assayed by blind analysis of the lung sections. A 6‐fold decrease in the number of prominent endothelial cells—suspected to be indicative of cellular activation and inflammatory response—was observed in lung sections derived from mice treated with bleomycin and EPO compared to animals injected with bleomycin alone (p < 0.008). Additionally, there was twice the number of ICAM1‐positive endothelial cells in animals treated with bleomycin alone compared with the number in the bleomycin and EPO‐treated group (p < 0.05). Alveolar mononuclear phagocytic hyperplasia was reduced by as much as 100% in animals treated with bleomycin and EPO compared to animals treated with bleomycin alone (p < 0.03). Finally, a 5‐fold decrease in interstitial fibrosis was observed in lung sections obtained from animals treated with bleomycin and EPO (p < 0.02). We conclude that EPO can ameliorate drug‐induced fibrosis and endothelial damage caused by chemotherapeutic agents. © 2008 Wiley‐Liss, Inc.

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“…The Epo-activated PI3K/AKT signaling pathway has been recently involved in erythroid differentiation. 44,45 Ghaffari et al 46 brought also arguments showing that AKT function is required for regulation of erythroid differentiation. In view of these reports, our data showing an activation of AKT following Spi-1 down-regulation and erythroid differentiation are particularly interesting, and our model will be fruitful to investigate the relationship between Spi-1 differentiation blockage and AKT function.…”

Section: Discussionmentioning

confidence: 99%

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

Rimmelé

Kosmider

Mayeux

et al. 2006

Blood

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Overexpression of the transcription factor Spi-1/PU.1 in mice leads to acute erythroleukemia characterized by a differentiation block at the proerythroblastic stage. In this study, we made use of a new cellular system allowing us to reach graded expression of Spi-1 in preleukemic cells to dissect mechanisms of Spi-1/ PU-1 in erythroleukemogenesis. This system is based on conditional production of 1 or 2 spi-1-interfering RNAs stably inserted into spi-1 transgenic proerythroblasts. We show that Spi-1 knock-down was sufficient to reinstate the erythroid differentiation program. This differentiation process was associated with an exit from the cell cycle. Evidence is provided that in the presence of erythropoietin (Epo), Spi-1 displays an antiapoptotic role that is independent of its function in blocking erythroid differentiation. IntroductionThe ETS family transcription factor Spi-1/PU.1 plays a crucial role in hematopoiesis by determining cell fate through a temporal and spatial control of its expression and activity. Besides its role in myelopoiesis and B lymphopoiesis, 1,2 Spi-1/PU.1 participates to the self-renewal of hematopoietic stem cells. 3-6 PU.1 is expressed in erythroid progenitors and is silenced at an early stage of both fetal and adult erythropoiesis. 7,8 With regard to its role in erythropoiesis, conflicting hypotheses are reported. Fisher et al 9,10 brought argument, suggesting that PU.1 is required for erythropoiesis in adult bone marrow but not in fetal liver. Others showed that PU.1 is involved in the self-renewal of fetal erythroid progenitors, 7 whereas its role in erythroid progenitors from the adult seemed to be excluded. 5 A dysregulation of PU.1 activity can lead to murine malignant hemopathies. Rosenbauer et al, 11 by creating a hypomorphic function, reduced PU.1 expression by 80%, and established an association between PU.1 and the occurrence of acute myeloid leukemia (AML). This report led to the concept that a decrease to a critical threshold level of PU.1 activity, rather than a complete abrogation, contributes to AML pathogenesis. Other publications describing deletion of one PU.1 allele associated with mutations of the other allele leading to reduction in the function of the protein corroborated this paradigm. 12,13 However, a recent study in which the function of PU.1 was examined in adult hematopoiesis using conditional gene targeting describes the development of AML in the absence of PU.1 expression. 14 In contrast to the myeloid lineage, a high expression of spi-1 is oncogenic in the erythroid lineage. 15 In transgenic mice, Spi-1 overexpression leads to the development of severe anemia and hepatosplenomegaly resulting from the proliferation of proerythroblasts blocked in differentiation. 16 At the disease onset, survival and growth of spi-1 transgenic proerythroblasts remain under erythropoietin (Epo) control. Later on, spi-1-transgenic proerythroblasts lose their Epo requirement for proliferation and become tumorigenic. This malignant phenotype requires additional genetics e...

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Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway

Cited by 172 publications

References 72 publications

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

Erythropoietin ameliorates chemotherapy‐induced fibrosis of the lungs in a preclinical murine model

Spi-1/PU.1 participates in erythroleukemogenesis by inhibiting apoptosis in cooperation with Epo signaling and by blocking erythroid differentiation

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