Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism

Kaku, Hiroaki; Rothstein, Thomas L.

doi:10.4049/jimmunol.0901988

Cited by 18 publications

(12 citation statements)

References 30 publications

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“… 23 The mechanism by which FAIM-S expression is regulated in B cells has recently been described. 43 However, the regulation of FAIM-L expression has not been resolved. We have reported on the roles of the two isoforms in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

et al. 2015

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The brains of patients with Alzheimer's disease (AD) present elevated levels of tumor necrosis factor-α (TNFα), a cytokine that has a dual function in neuronal cells. On one hand, TNFα can activate neuronal apoptosis, and on the other hand, it can protect these cells against amyloid-β (Aβ) toxicity. Given the dual behavior of this molecule, there is some controversy regarding its contribution to the pathogenesis of AD. Here we examined the relevance of the long form of Fas apoptotic inhibitory molecule (FAIM) protein, FAIM-L, in regulating the dual function of TNFα. We detected that FAIM-L was reduced in the hippocampi of patients with AD. We also observed that the entorhinal and hippocampal cortex of a mouse model of AD (PS1M146LxAPP751sl) showed a reduction in this protein before the onset of neurodegeneration. Notably, cultured neurons treated with the cortical soluble fractions of these animals showed a decrease in endogenous FAIM-L, an effect that is mimicked by the treatment with Aβ-derived diffusible ligands (ADDLs). The reduction in the expression of FAIM-L is associated with the progression of the neurodegeneration by changing the inflammatory response mediated by TNFα in neurons. In this sense, we also demonstrate that the protection afforded by TNFα against Aβ toxicity ceases when endogenous FAIM-L is reduced by short hairpin RNA (shRNA) or by treatment with ADDLs. All together, these results support the notion that levels of FAIM-L contribute to determine the protective or deleterious effect of TNFα in neuronal cells.

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Section: Discussionmentioning

confidence: 99%

Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

et al. 2015

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“…Interestingly, TWIST1 cooperates with HOXA5 to downregulate the transcription of TP53 (Stasinopoulos et al , 2005) and counteracts MYC‐induced apoptosis when strongly overexpressed in solid tumour cells (Valsesia‐Wittmann et al , 2004). Thus, TWIST1 and FAIM (regulated by IRF4; Kaku & Rothstein, 2009) are interesting candidates for the observed block of apoptosis in MLL‐AFF1 expressing cells.…”

Section: Potential Functions Of the Mll‐af4 And Af4‐mll Fusion Proteimentioning

confidence: 99%

Mechanisms of leukemogenesis by MLL fusion proteins

2010

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SummaryInfant acute leukaemia is characterised by specific genetic rearrangements and a rapid onset of disease shortly after birth. The vast majority of these cases bear rearranged MLL alleles. However, many facets of MLL-rearranged leukaemia are largely unknown. Basically, there exists a fundamental and evolutionary conserved relationship between the family of MLL/ Trithorax proteins and the regulation of HOX gene clusters. Therefore, direct MLL fusion proteins are per se able to deregulate HOX genes, except when reciprocal MLL fusion proteins come into play. This reviews discusses (i) the current situation in MLL-rearranged leukaemia, (ii) the molecular and genetic tools to functionally investigate the many different MLL fusions, (iii) the latency of disease development, (iv) a novel cancer mechanism that has been recently uncovered when different MLL fusion protein complexes were characterized, (v) mutated signalling pathways in MLL-rearranged leukaemia and (vi) presents new ideas on how a given MLL fusion protein may modulate existing signalling pathways in leukaemic cells. The hypothesis is posed that the many different fusion partners of MLL are critically distinct entities for which specific inhibitors should be identified in the future.

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“…IRF4 has been found to induce c-Myc expression in multiple myeloma cells and is critical for their survival and expansion [15] . Finally, IRF4 can induce the expression of Fas apoptosis inhibitory molecule (FAIM) to regulate mature B cell survival and apoptosis [16] .…”

Section: Introductionmentioning

confidence: 99%

IRF4 Is a Suppressor of c-Myc Induced B Cell Leukemia

Pathak

Trinh

et al. 2011

PLoS ONE

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Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4+/−Myc); the average age of mortality in the IRF4+/−Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4+/−Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4+/−Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27kip is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27kip was lost in the IRF4+/−Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27kip and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice.

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Fas Apoptosis Inhibitory Molecule Expression in B Cells Is Regulated through IRF4 in a Feed-Forward Mechanism

Cited by 18 publications

References 30 publications

Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

Amyloid-β reduces the expression of neuronal FAIM-L, thereby shifting the inflammatory response mediated by TNFα from neuronal protection to death

Mechanisms of leukemogenesis by MLL fusion proteins

IRF4 Is a Suppressor of c-Myc Induced B Cell Leukemia

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