Cytokines Direct the Regulation of Bim mRNA Stability by Heat-Shock Cognate Protein 70

Matsui, Hirotaka; Asou, Hiroya; Inaba, Toshiya

doi:10.1016/j.molcel.2006.12.007

Cited by 95 publications

(81 citation statements)

References 43 publications

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“…Compared with IL3 withdrawn Bcl-2-expressing cells treated with control shRNAi, cells treated with each autophagy-gene shRNAi showed greatly reduced levels of Bim mRNA both at 12 and 24 h after IL3 deprivation ( Figure 10D). Therefore, although Chop may regulate several proapoptotic proteins after growth factor withdrawal, autophagy specifically suppressed Chop-dependent Bim induction or mRNA stabilization (Matsui et al, 2007).…”

Section: Autophagy Specifically Regulates the Proapoptotic Protein Bimentioning

confidence: 99%

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

Altman¹,

Wofford²,

Zhao³

et al. 2009

MBoC

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Tissue homeostasis is controlled by the availability of growth factors, which sustain exogenous nutrient uptake and prevent apoptosis. Although autophagy can provide an alternate intracellular nutrient source to support essential basal metabolism of apoptosis-resistant growth factor-withdrawn cells, antiapoptotic Bcl-2 family proteins can suppress autophagy in some settings. Thus, the role of autophagy and interactions between autophagy and apoptosis in growth factor-withdrawn cells expressing Bcl-2 or Bcl-xL were unclear. Here we show autophagy was rapidly induced in hematopoietic cells upon growth factor withdrawal regardless of Bcl-2 or Bcl-xL expression and led to increased mitochondrial lipid oxidation. Deficiency in autophagy-essential gene expression, however, did not lead to metabolic catastrophe and rapid death of growth factor-deprived cells. Rather, inhibition of autophagy enhanced survival of cells with moderate Bcl-2 expression for greater than 1 wk, indicating that autophagy promoted cell death in this time frame. Cell death was not autophagic, but apoptotic, and relied on Chop-dependent induction of the proapoptotic Bcl-2 family protein Bim. Therefore, although ultimately important, autophagy-derived nutrients appear initially nonessential after growth factor withdrawal. Instead, autophagy promotes tissue homeostasis by sensitizing cells to apoptosis to ensure only the most apoptosis-resistant cells survive long-term using autophagy-derived nutrients when growth factor deprived. INTRODUCTIONMetazoan cells require growth factor input to maintain metabolism and viability in both development and tissue homeostasis (Raff, 1992;Rathmell et al., 2000). The phosphoinositide 3-kinase (PI3K)-Akt mammalian target of rapamycin (mTOR) pathway is an important signaling mechanism of many growth factors that maintains nutrient uptake and prevents apoptotic cell death (Vivanco and Sawyers, 2002;Wieman et al., 2007). When cells are deprived of appropriate growth factor stimulation, the loss of PI3K-AktmTOR signaling, glucose transporter localization on the cell surface, and glucose uptake leads to apoptosis or autophagy (Tsujimoto and Shimizu, 2005;Wieman et al., 2007). Unlike the cell death pathway of apoptosis, autophagy is a dualfunction mechanism of bulk cytoplasmic and organelle degradation in lysosomes that can promote cell survival if controlled or can lead to death if excessive. The regulation of autophagy and how it impacts apoptosis and cell fate upon growth factor withdrawal, however, remain uncertain.Autophagy may influence cell fate upon growth factor deprivation by multiple mechanisms. Regulated autophagy can promote cell survival by providing metabolic fuel for mitochondrial oxidation after lysosomal digestion of intracellular components (Eskelinen, 2005;Lum et al., 2005b). Indeed, cells incapable of apoptosis can survive for an extended time after growth factor withdrawal or nutrient deprivation by utilizing autophagy as a source of nutrients to support basal cell metabolism (Lum et al., 2005a;Dege...

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Section: Autophagy Specifically Regulates the Proapoptotic Protein Bimentioning

confidence: 99%

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

Altman¹,

Wofford²,

Zhao³

et al. 2009

MBoC

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“…At the transcriptional level, the promoter of the Bim gene is activated by stress-inducible transcription factors including activator protein 1 and forkhead box protein O. 4,7,8 Post-transcriptional mechanisms that have been shown to control Bim expression levels include both mRNA stability 9 and protein stability. [10][11][12] Signaling downstream of receptor tyrosine kinases (RTKs) including epidermal growth factor receptor induce the proteasomal degradation of Bim.…”

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confidence: 99%

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

et al. 2013

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“…Bim transcript and protein expression was induced as soon as 26 h after dox treatment ( Supplementary Figures 2A and B), showing that the regulation of Bim expression occurs first at the transcriptional level. As Bim mRNA can be stabilized through binding of the heat-shock cognate 70 to the Bim 3 0 -UTR, 27 (Figure 6a). Thus, the inhibition of Bim expression by Spi-1 occurs at the level of the initiation of transcription.…”

Section: Spi-1 Decreases Bim Expression In Preleukaemic Cellsmentioning

confidence: 99%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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Cytokines Direct the Regulation of Bim mRNA Stability by Heat-Shock Cognate Protein 70

Cited by 95 publications

References 43 publications

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

Autophagy Provides Nutrients but Can Lead to Chop-dependent Induction of Bim to Sensitize Growth Factor–deprived Cells to Apoptosis

BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by βTrCP1

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

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