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ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis.

ABSTRACT: Lineage specification and cellular maturation require coordinated regulation of gene expression programs. In large part, this is dependent on the activator and repressor functions of protein complexes associated with tissue-specific transcriptional regulators. In this study, we have used a proteomic approach to characterize multiprotein complexes containing the key hematopoietic regulator SCL in erythroid and megakaryocytic cell lines. One of the novel SCL-interacting proteins identified in both cell types is the transcriptional corepressor ETO-2. Interaction between endogenous proteins was confirmed in primary cells. We then showed that SCL complexes are shared but also significantly differ in the two cell types. Importantly, SCL/ETO-2 interacts with another corepressor, Gfi-1b, in red cells but not megakaryocytes. The SCL/ETO-2/Gfi-1b association is lost during erythroid differentiation of primary fetal liver cells. Genetic studies of erythroid cells show that ETO-2 exerts a repressor effect on SCL target genes. We suggest that, through its association with SCL, ETO-2 represses gene expression in the early stages of erythroid differentiation and that alleviation/modulation of the repressive state is then required for expression of genes necessary for terminal erythroid maturation to proceed.

SUBMITTER: Schuh AH

PROVIDER: S-EPMC1291220 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis.

Schuh Anna H AH Tipping Alex J AJ Clark Allison J AJ Hamlett Isla I Guyot Boris B Iborra Francesco J FJ Rodriguez Patrick P Strouboulis John J Enver Tariq T Vyas Paresh P Porcher Catherine C

Molecular and cellular biology 20051201 23

Lineage specification and cellular maturation require coordinated regulation of gene expression programs. In large part, this is dependent on the activator and repressor functions of protein complexes associated with tissue-specific transcriptional regulators. In this study, we have used a proteomic approach to characterize multiprotein complexes containing the key hematopoietic regulator SCL in erythroid and megakaryocytic cell lines. One of the novel SCL-interacting proteins identified in both ...[more]

PMID: 16287841

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Project description:KITL/KIT can elicit diverse sets of signals within lymphoid, myeloid, mast, and erythroid lineages, and exert distinct effects on growth, survival, migration, adhesion, and secretory responses. Presently, we have applied a PY-mutant allele knockin approach to specifically assess possible roles for KIT-PY567 and KIT-PY719 sites, and coupled pathways, during erythropoiesis.Mouse models used to investigate this problem include those harboring knocked-in KIT(Y567F/Y567F), KIT(Y569F/Y569F), KIT(Y719F,Y719F), and KIT(Y567F/Y567F:Y569F/Y569F) alleles. The erythron was stressed by myelosuppression using 5-fluorouracil, and by phenylhydrazine-induced hemolysis. In addition, optimized systems for ex vivo analyses of bone marrow and splenic erythropoiesis were employed to more directly analyze possible stage-specific effects on erythroid cell growth, survival, development and KIT signaling events.In Kit(Y567F/Y567F) mice, steady-state erythropoiesis was unperturbed while recovery from anemia due to 5-fluorouracil or phenylhydrazine was markedly impaired. Deficiencies in erythroid progenitor expansion occurred both in the bone marrow and the spleen. Responses to chronic erythropoietin dosing were also compromised. Ex vivo, Kit(Y567F/Y567F) (pro)erythroblast development was skewed from a Kit(pos)CD71(high) stage toward a subsequent Kit(neg)CD71(high) compartment. Proliferation and, to an extent, survival capacities were also compromised. Similar stage-specific defects existed for erythroid progenitors from Kit(Y567F/Y567F:Y569F/Y569F) but not KIT(Y719F/Y719F) mice. Kit(Y567F/Y567F) erythroblasts were used further to analyze KIT-PY567-dependent signals. MEK-1,2/ERK-1,2 signaling was unaffected while AKT, p70S6K, and especially JNK2/p54 pathways were selectively attenuated.Nonredundant KIT-PY567-directed erythroblast-intrinsic signals are selectively critical for stress erythropoiesis. Investigations also add to an understanding of how KIT directs distinct outcomes among diverse progenitors and lineages.

Dataset Information

ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis.

Publications

ETO-2 associates with SCL in erythroid cells and megakaryocytes and provides repressor functions in erythropoiesis.

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