FOXO1 Transcription Factor: A Critical Effector of the PI3K-AKT Axis in B-Cell Development

Szydłowski, Maciej; Jabłońska, Ewa; Juszczyński, Przemysław

doi:10.3109/08830185.2014.885022

Cited by 60 publications

(47 citation statements)

References 70 publications

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“…Similarly, the maturation defect of SPPL2a 2/2 B cells was not reverted by a Bcl-2 transgene (20). As mentioned above, the FOXO transcription factors are major effectors of the PI3K/Akt pathway (41). In murine primary B cells, FOXO overexpression has been shown to cause cell cycle arrest and increased apoptosis (66) by regulating target genes involved in these processes (67).…”

Section: Discussionmentioning

confidence: 99%

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Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Hüttl

Kläsener

Schweizer

et al. 2015

The Journal of Immunology

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The invariant chain (CD74), a chaperone in MHC class II–mediated Ag presentation, is sequentially processed by different endosomal proteases. We reported recently that clearance of the final membrane-bound N-terminal fragment (NTF) of CD74 is mediated by the intramembrane protease signal peptide peptidase-like (SPPL)2a, a process critical for B cell development. In mice, SPPL2a deficiency provokes the accumulation of this NTF in endocytic vesicles, which leads to a B cell maturation arrest at the transitional 1 stage. To define the underlying mechanism, we analyzed the impact of SPPL2a deficiency on signaling pathways involved in B cell homeostasis. We demonstrate that tonic as well as BCR-induced activation of the PI3K/Akt pathway is massively compromised in SPPL2a−/− B cells and identify this as major cause of the B cell maturation defect in these mice. Altered BCR trafficking induces a reduction of surface IgM in SPPL2a-deficient B cells, leading to a diminished signal transmission via the BCR and the tyrosine kinase Syk. We provide evidence that in SPPL2a−/− mice impaired BCR signaling is to a great extent provoked by the accumulating CD74 NTF, which can interact with the BCR and Syk, and that impaired PI3K/Akt signaling and reduced surface IgM are not directly linked processes. In line with disturbances in PI3K/Akt signaling, SPPL2a−/− B cells show a dysregulation of the transcription factor FOXO1, causing elevated transcription of proapoptotic genes. We conclude that SPPL2a-mediated processing of CD74 NTF is indispensable to maintain appropriate levels of tonic BCR signaling to promote B cell maturation.

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Section: Discussionmentioning

confidence: 99%

“…The kinase Akt phosphorylates several downstream targets, including the FOXO family of transcription factors (40,41). In resting B lymphocytes, FOXO proteins reside in the nucleus and drive the transcription of cell cycle-regulating genes.…”

Section: B Cells Of Sppl2amentioning

confidence: 99%

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Hüttl

Kläsener

Schweizer

et al. 2015

The Journal of Immunology

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“…As we all know, CD19 signalling induces PI3K activation and Foxo1 is a critical effector of the PI3K‐AKT axis in B‐cell development 29. Thus, we tested whether Foxo1 mediated CD19‐controlled ADAM28 expression in MZP.…”

Section: Resultsmentioning

confidence: 99%

CD19 regulates ADAM28‐mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells

Zhu

Xiao²,

Liu³

et al. 2017

J Cellular Molecular Medi

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As the first line of defence, marginal zone (MZ) B cells play principal roles in clearing blood‐borne pathogens during infection and are over‐primed in autoimmune diseases. However, the basic mechanisms underlying MZ B‐cell development are still unclear. We found here that CD19 deficiency blocked the differentiation of marginal zone precursors (MZP) to MZ B cells, whereas CD19 expression in CD19‐deficient MZP rescues MZ B‐cell generation. Furthermore, CD19 regulates Notch2 cleavage by up‐regulating ADAM28 expression in MZP. Finally, we found that CD19 suppressed Foxo1 expression to promote ADAM28 expression in MZP. These results suggest that CD19 controls the differentiation of MZP to MZ B cells by regulating ADAM28‐mediated Notch2 cleavage. Thus, we demonstrated the basic mechanisms underlying the differentiation of MZP to MZ B cells.

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“…FOXOs control diverse cellular processes, such as apoptosis, cell cycle, DNA damage repair, oxidative stress, or glucose metabolism. 17,18 FOXO1 plays an essential role in B-cell development by inducing the expression of genes critical for progression through the consecutive steps of differentiation. 18 In mature B lymphocytes, BCR-induced activation of PI3K-AKT kinases and subsequent phosphorylation and inactivation of FOXO1 decreases expression of FOXO1 target genes, including proapoptotic BH3-only protein BCL2L11 (BIM) and cell cycle inhibitor CDKN1B (p27 Kip1 ).…”

Section: Introductionmentioning

confidence: 99%

“…17,18 FOXO1 plays an essential role in B-cell development by inducing the expression of genes critical for progression through the consecutive steps of differentiation. 18 In mature B lymphocytes, BCR-induced activation of PI3K-AKT kinases and subsequent phosphorylation and inactivation of FOXO1 decreases expression of FOXO1 target genes, including proapoptotic BH3-only protein BCL2L11 (BIM) and cell cycle inhibitor CDKN1B (p27 Kip1 ). 19 In murine models, conditional deletion of FOXO1 protected quiescent peripheral B cells from apoptosis mediated by inducible loss of the BCR.…”

Section: Introductionmentioning

confidence: 99%

FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas

Szydłowski

Kiliszek

Sewastianik

et al. 2016

Blood

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Inhibition of spleen tyrosine kinase (SYK) in tonic B-cell receptor (BCR) signal-dependent diffuse large B-cell lymphomas (DLBCLs) inhibits cellular proliferation, decreases cholesterol biosynthesis, and triggers apoptosis, at least in part via a mechanism involving decreased activity of phosphatidylinositol 3-kinase/AKT axis. Because forkhead box O1 (FOXO1) is a major effector of this pathway, we investigated the role of FOXO1 in toxicity of BCR pathway inhibition. Inhibition of SYK in DLBCL cells with tonic BCR signaling decreased phospho-AKT and phospho-FOXO1 levels and triggered FOXO1-driven gene expression. Introduction of constitutively active FOXO1 mutant triggered cell cycle arrest and apoptosis, indicating that increased FOXO1 activity is toxic to these DLBCL cells. Depletion of FOXO1 with short hairpin RNA led to almost complete resistance to chemical SYK inhibitor R406, demonstrating that FOXO1 is also required for R406-induced cell death. FOXO1 in these cells is also involved in regulation of expression of the critical master regulator of cholesterol biosynthesis, SREBP1. Because HRK is the key effector of SYK inhibition, we characterized a mechanism linking FOXO1 activation and HRK induction that involves caspase-dependent cleavage of HRK's transcriptional repressor DREAM. Because AKT in lymphoma cells can be regulated by other signals than BCR, we assessed the combined effects of the AKT inhibitor MK-2206 with R406 and found markedly synergistic FOXO1-dependent toxicity. In primary DLBCLs, FOXO1 expression was present in 80% of tumors, correlated with SYK activity, and was associated with longer overall survival. These results demonstrate that FOXO1 is required for SYK and AKT inhibitor-induced toxicity. (Blood. 2016;127(6):739-748)

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FOXO1 Transcription Factor: A Critical Effector of the PI3K-AKT Axis in B-Cell Development

Cited by 60 publications

References 70 publications

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

Processing of CD74 by the Intramembrane Protease SPPL2a Is Critical for B Cell Receptor Signaling in Transitional B Cells

CD19 regulates ADAM28‐mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells

FOXO1 activation is an effector of SYK and AKT inhibition in tonic BCR signal-dependent diffuse large B-cell lymphomas

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