Subtle distinct regulations of late erythroid molecular events by PI3K/AKT-mediated activation of Spi-1/PU.1 oncogene autoregulation loop

Breig, Osman; Théoleyre, Orianne; Douablin, Alexandre; Baklouti, Faouzi

doi:10.1038/onc.2010.29

Cited by 15 publications

(23 citation statements)

References 41 publications

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“…In particular, phosphorylation of SRSF5 in response to the PI3K signaling pathway has been shown to be associated with a change in alternative splicing [28]–[30]. Our recent data have also demonstrated that inhibition of the PI3K/AKT pathway using LY294002 is sufficient to activate the erythroid splicing of 4.1R exon 16 [31]. We therefore tested the impact of LY294002-mediated inhibition of the PI3K/AKT signaling cascade in cells overexpressing SRSF5.…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblotting experiments revealed a clear decrease in SRSF5 epitopes (Figure 7A). knowing that inhibition of the PI3K/AKT signaling cascade triggers MEL cell erythroid differentiation [31], it would be difficult to conclude whether SRSF5 downregulation is a direct effect of a phosphorylation suppression due to PI3K/AKT inhibition, or an indirect effect of induced cell differentiation.…”

Section: Resultsmentioning

confidence: 99%

“…Immunoblot analysis of SRSF5 expression was revealed by anti-SRSF5 antibody (pAb-SRSF5). The decrease in SRSF5 accumulation is most likely secondary to cell differentiation triggered by PI3K/AKT inhibition [31]. Grb2 immunoblot served as control.…”

Section: Resultsmentioning

confidence: 99%

“…Cells were cultured either in the absence (uninduced) or presence of DMSO (+DMSO) or PI3K inhibitor LY294002 (+LY29) for 4 days. Both agents trigger cell erythroid differentiation [31]. Exon 16 splicing was analyzed in untransfected cells (1), cells transfected with mock vector containing only EGFP (2), and in cells transfected with a recombinant vector overexpressing the fusion protein EGFP-SRSF5 (3).…”

Section: Resultsmentioning

confidence: 99%

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Proteasome-Mediated Proteolysis of SRSF5 Splicing Factor Intriguingly Co-occurs with SRSF5 mRNA Upregulation during Late Erythroid Differentiation

Breig

Baklouti

2013

PLoS ONE

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SR proteins exhibit diverse functions ranging from their role in constitutive and alternative splicing, to virtually all aspects of mRNA metabolism. These findings have attracted growing interest in deciphering the regulatory mechanisms that control the tissue-specific expression of these SR proteins. In this study, we show that SRSF5 protein decreases drastically during erythroid cell differentiation, contrasting with a concomitant upregulation of SRSF5 mRNA level. Proteasome chemical inhibition provided strong evidence that endogenous SRSF5 protein, as well as protein deriving from stably transfected SRSF5 cDNA, are both targeted to proteolysis as the cells undergo terminal differentiation. Consistently, functional experiments show that overexpression of SRSF5 enhances a specific endogenous pre-mRNA splicing event in proliferating cells, but not in differentiating cells, due to proteasome-mediated targeting of both endogenous and transfection-derived SRSF5. Further investigation of the relationship between SRSF5 structure and its post-translation regulation and function, suggested that the RNA recognition motifs of SRSF5 are sufficient to activate pre-mRNA splicing, whereas proteasome-mediated proteolysis of SRSF5 requires the presence of the C-terminal RS domain of the protein. Phosphorylation of SR proteins is a key post-translation regulation that promotes their activity and subcellular availability. We here show that inhibition of the CDC2-like kinase (CLK) family and mutation of the AKT phosphorylation site Ser86 on SRSF5, have no effect on SRSF5 stability. We reasoned that at least AKT and CLK signaling pathways are not involved in proteasome-induced turnover of SRSF5 during late erythroid development.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Proteasome-Mediated Proteolysis of SRSF5 Splicing Factor Intriguingly Co-occurs with SRSF5 mRNA Upregulation during Late Erythroid Differentiation

Breig

Baklouti

2013

PLoS ONE

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“…50 PU.1 expression and activation is controlled by several intracellular signal transduction events, including induction of PI3K/AKT and Src signaling pathways. 51,52 Because these pathways are activated by EP1 and EP3 signaling, 53,54 and because our data identified that PGE 2 regulates Flt3L-dependent DC development through the EP1 and EP3 receptors, it is possible that PGE 2 -mediated induction of PI3K/AKT and Src signaling pathways regulates PU.1 expression in DC-committed progenitors that leads to increased expression of Flt3. However, in other progenitor lineages change in transcription factor activities in the absence of change in expression has been reported.…”

mentioning

confidence: 89%

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Singh

Hoggatt

et al. 2012

Blood

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Dendritic cell (DC) homeostasis, like all mature blood cells, is maintained via hierarchal generation from hematopoietic precursors; however, little is known about the regulatory mechanisms governing DC generation. Here, we show that prostaglandin E 2 (PGE 2 ) is required for optimal IntroductionDendritic cells (DCs) are specialized Ag-presenting immune cells that induce adaptive immune responses and maintain self-tolerance and are attractive targets for therapeutic manipulation of the immune system. 1,2 Two main DC subsets have been identified on the basis of their location, phenotype, and function: Ag-presenting classic DC (cDC) and type I IFN-producing plasmacytoid DC (pDC), 3,4 and are generated from Flt3-expressing hematopoietic progenitor cells in the BM. 5,6 Recent studies identified a common DC, monocyte and macrophage precursor designated as macrophage DC progenitor cell (MDP) 7,8 and a common DC progenitor (CDP) that is restricted to DC development. 9 MDPs differentiate to CDPs, which in turn give rise to cDCs and pDCs, but not monocytes, and finally to pre-cDCs, 10 a committed precursor of cDCs. 11,12 Unlike MDPs and CDPs that differentiate within the BM, pre-cDCs traffic to secondary lymphoid organs where they further differentiate into cDCs. 4,13 In addition, monocytes can also develop a DC phenotype under inflammatory conditions. 14,15 Flt3 (also known as Flk2 and CD135) is a receptor tyrosine kinase that is broadly expressed on early BM hematopoietic progenitor cells (HPCs), including DC progenitor cells. 5,9,16 Mice with a deficiency in Flt3 or Flt3 ligand (Flt3L) have reduced DC numbers, 13,17 whereas administration of Flt3L dramatically increases BM and peripheral DCs. 18 Although Flt3 signaling is crucial for DC generation from their progenitor cells at steady state, the normal physiologic mechanisms that control Flt3 expression and regulate Flt3L-dependent DC differentiation remain poorly understood.Prostaglandin E 2 (PGE 2 ) is the predominant metabolite of arachidonic acid metabolism produced through the sequential action of phospholipase A 2 , cyclooxygenases (COXs), and PGE synthase. 19,20 There are 2 functionally distinct COX enzyme isoforms, COX1 and COX2, that are encoded by different genes. 20 PGE 2 has been shown to modulate HPC differentiation, inhibiting CFU-GM 21-23 but promoting erythroid burst-forming unit and granulocyte, erythroid, megakaryocyte, and macrophage CFU. 24,25 The long-acting PGE 2 analog, 16,16-dimethyl-PGE 2 (dmPGE 2 ) was shown to increase HSC frequency and engraftment 26,27 and to enhance HSC survival, proliferation, and homing to the BM. 27 Thus, PGE 2 regulates self-renewal and differentiation of HSCs and HPCs, and its effects can differ, depending on hematopoietic cell type and stage of differentiation.The role of PGE 2 in DC maturation and migration under inflammatory conditions is well known. PGE 2 promotes the migration of monocyte-derived and Langerhans DCs, increases their expression of costimulatory molecules, and enhances their ability to stimulate T...

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Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis

Morinière¹,

Delhommeau²,

Calender³

et al. 2010

Blood Cells, Molecules, and Diseases

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Subtle distinct regulations of late erythroid molecular events by PI3K/AKT-mediated activation of Spi-1/PU.1 oncogene autoregulation loop

Cited by 15 publications

References 41 publications

Proteasome-Mediated Proteolysis of SRSF5 Splicing Factor Intriguingly Co-occurs with SRSF5 mRNA Upregulation during Late Erythroid Differentiation

Proteasome-Mediated Proteolysis of SRSF5 Splicing Factor Intriguingly Co-occurs with SRSF5 mRNA Upregulation during Late Erythroid Differentiation

Blockade of prostaglandin E2 signaling through EP1 and EP3 receptors attenuates Flt3L-dependent dendritic cell development from hematopoietic progenitor cells

Nonsense-mediated mRNA decay (NMD) blockage promotes nonsense mRNA stabilization in protein 4.1R deficient cells carrying the 4.1R Coimbra variant of hereditary elliptocytosis

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