Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation

Grech, Godfrey; Blázquez-Domingo, Montserrat; Kolbus, Andrea; Bakker, Walbert J.; Müllner, Ernst W.; Beug, Hartmut; Lindern, Marieke von

doi:10.1182/blood-2008-01-133140

Cited by 37 publications

(64 citation statements)

References 82 publications

(100 reference statements)

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“…The biological consequences predicted by these abnormalities are consistent with the Gata1 low phenotype. Alterations of TGF-b signaling predict increased levels of osteoblast differentiation in BM but not in spleen from Gata1 low mice, increased apoptosis and G1 arrest both in BM and spleen but reduced ubiquitin-mediated proteolysis, a pathway indispensable for erythroid maturation, 36 in BM only and activation of mammalian target of rapamycin (mTOR), a positive regulator of translation which improves erythropoiesis, 37 in spleen (Table 5). …”

Section: Gata1mentioning

confidence: 99%

Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

Zingariello¹,

Martelli

Ciaffoni

et al. 2013

Blood

119

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Section: Gata1mentioning

confidence: 99%

Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

Zingariello¹,

Martelli

Ciaffoni

et al. 2013

Blood

119

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“…Moreover, we found preferential translation of transcripts that depend on SCF-induced PI3K activation (eg, Use1 and Nap1l1). 17 The translation of these transcripts is under the control of the mTOR pathway, and mTOR activity also enhances the translation of 5Ј-terminal oligopyrimidine tract mRNAs. 36 After Rps19 and Rpl11 knockdown, we harvested polysomal RNA from cells cultured in the presence of SCF.…”

mentioning

confidence: 99%

“…Quantitative RT-PCR (qRT-PCR) was performed as described previously. 17 Primers are listed in supplemental Table 4. For mouse erythroblasts, ␤-tubulin was used as a control; for human erythroblasts, B2M selected from a set of 32 endogenous controls was used (Applied Biosystems).…”

mentioning

confidence: 99%

“…16 We have shown previously that expansion of erythroblasts depends on the SCF-induced availability of eIF4E, which is required for the translation of specific transcripts with a complex RNA structure such as Igbp1 and Use1. 17 The scanning complex includes the small ribosomal subunit, and the 60S subunit joins at the AUG start codon. 16 We hypothesized that the reduced availability of ribosomal subunits in DBA, similar to the availability of eIF4E, may affect translation initiation of specific transcripts important for erythroid development.…”

mentioning

confidence: 99%

“…19 RNA isolation, cDNA synthesis, and qRT-PCR In vitro-synthesized luciferase RNA was added to each fraction of the sucrose gradient to control for RNA-isolation efficiency from the distinct fractions. RNA was isolated from gradient fractions as described previously, 17 and further purified with LiCl. 20 Total RNA was isolated using the RNeasy Mini or Micro (for BM cells) Kit (QIAGEN).…”

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confidence: 99%

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Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts

Horos

IJspeert

Pospı́šilová

et al. 2012

Blood

Self Cite

168

218

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Diamond-Blackfan anemia (DBA) is associated with developmental defects and profound anemia. Mutations in genes encoding a ribosomal protein of the small (eg, RPS19) or large (eg, RPL11) ribosomal subunit are found in more than half of these patients. The mutations cause ribosomal haploinsufficiency, which reduces overall translation efficiency of cellular mRNAs. We reduced the expression of Rps19 or Rpl11 in mouse erythroblasts and investigated mRNA polyribosome association, which revealed deregulated translation initiation of specific transcripts. Among these were Bag1, encoding a Hsp70 cochaperone, and Csde1, encoding an RNA-binding protein, and both were expressed at increased levels in erythroblasts. Their translation initiation is cap independent and starts from an internal ribosomal entry site, which appeared sensitive to knockdown of Rps19 or Rpl11. Mouse embryos lacking Bag1 die at embryonic day 13.5, with reduced erythroid colony forming cells in the fetal liver, and low Bag1 expression impairs erythroid differentiation in vitro. Reduced expression of Csde1 impairs the proliferation and differentiation of erythroid blasts. Protein but not mRNA expression of BAG1 and CSDE1 was reduced in erythroblasts cultured from DBA patients. Our data suggest that impaired internal ribosomal entry site-mediated translation of mRNAs expressed at increased levels in erythroblasts contributes to the erythroid phenotype of DBA. IntroductionDiamond-Blackfan anemia (DBA) presents as normochromic, macrocytic anemia with reduced erythroid precursors in the BM. 1 Approximately half of DBA patients have skeletal abnormalities such as thumb malformations and growth retardation. 2 DBA is mostly diagnosed in infants less than 1 year of age, but in recent years, nonclassic cases of DBA are being diagnosed in adult patients. 1 DBA is associated with mutations in genes encoding ribosomal proteins in 55% of patients. 3 The most prominently mutated gene (in 25% of patients) is RPS19, 4 but mutations in RPS7, RPS10, RPS17, RPS24, and RPS26 in the small ribosomal subunit and in RPL5, RPL11, and RPL35A in the large ribosomal subunit have also been found. 3 The mutations cause haploinsufficiency of ribosomal proteins and lead to loss of ribosome function; this reduces general translation, as observed in lymphocytes derived from DBA patients. 5 Knockdown of RPS19 in hematopoietic progenitors either from human BM or cord blood decreases the colony-forming capacity of erythroid progenitors, whereas it affects the colony-forming capacity of myeloid progenitors to a far lesser extent. 6 Knockdown of Rps19 in mouse fetal liver-derived erythroblasts impairs their proliferation, but the differentiation of cells that survive the knockdown is not affected. 7 Because ribosome synthesis consumes up to 25% of a cell's energy, a disbalance in the synthesis of ribosomal proteins activates p53 and inhibits cell proliferation. 8 Free Rpl11 and Rpl5 bind and inhibit Mdm2, which reduces p53 ubiquitination and leads to its stabilization. Erythroid cells may ...

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FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

et al. 2014

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Ineffective erythropoiesis is observed in many erythroid disorders including β-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3−/− erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of β-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.

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Igbp1 is part of a positive feedback loop in stem cell factor–dependent, selective mRNA translation initiation inhibiting erythroid differentiation

Cited by 37 publications

References 82 publications

Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

Characterization of the TGF-β1 signaling abnormalities in the Gata1low mouse model of myelofibrosis

Ribosomal deficiencies in Diamond-Blackfan anemia impair translation of transcripts essential for differentiation of murine and human erythroblasts

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

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