Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor

Ghaffari, Saghi; Jagani, Zainab; Kitidis, Claire; Lodish, Harvey F.; Khosravi‐Far, Roya

doi:10.1073/pnas.0731871100

Cited by 135 publications

(129 citation statements)

References 40 publications

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“…The apoptosis induced in BaF3 cells upon either IL-3 withdrawal or expression of a FoxO3a triple mutant is not mediated through FasL signaling, however [170]. The FoxO3a target, BIM, is one mediator of apoptosis in response to IL-3 withdrawal or FoxO3a triple mutant expression.…”

Section: Multiple Functions Of the Foxo Transcription Factors: A Focumentioning

confidence: 99%

“…BCR-ABL transformation inhibits FoxO3a activity by maintaining PI3-K-dependent constitutive phosphorylation and cytoplasmic retention of FoxO3a [170,189]. Sustained activation of PI3-K/Akt by BCR-ABL in both BCR-ABL-transformed cells (Mo7e-p210 and BaF3-p210) and primary CML CD34+ cells leads to Skp2 transcriptional upregulation and likely contributes to leukemogenesis through enhanced proteasomal degradation and downregulation of FoxO protein levels [190].…”

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

“…Sustained activation of PI3-K/Akt by BCR-ABL in both BCR-ABL-transformed cells (Mo7e-p210 and BaF3-p210) and primary CML CD34+ cells leads to Skp2 transcriptional upregulation and likely contributes to leukemogenesis through enhanced proteasomal degradation and downregulation of FoxO protein levels [190]. One of the consequences of FoxO3a inhibition by BCR-ABL is the suppression of the downstream pro-apoptotic target TRAIL [170]. FoxO3a inhibition plays an important role in governing BCR-ABL-induced transformation as expression of a constitutively active FoxO3a triple mutant in BCR-ABL-transformed cells overrides growth factor-independent survival and induces apoptosis [169,170].…”

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

“…The suppression of BIM as a consequence of FoxO inhibition is an important, but not exclusive pathway governing hematopoietic cell survival. The TNF-related apoptosis inducing ligand, (TRAIL) which induces apoptosis via the extrinsic death-receptor mediated pathway is yet another target of FoxO3a that is suppressed during hematopoietic cell survival promoted by the cytokines IL-3, GM-CSF, and Epo [170].…”

Section: Multiple Functions Of the Foxo Transcription Factors: A Focumentioning

confidence: 99%

“…One of the consequences of FoxO3a inhibition by BCR-ABL is the suppression of the downstream pro-apoptotic target TRAIL [170]. FoxO3a inhibition plays an important role in governing BCR-ABL-induced transformation as expression of a constitutively active FoxO3a triple mutant in BCR-ABL-transformed cells overrides growth factor-independent survival and induces apoptosis [169,170]. The BH3-only pro-apoptotic protein BIM is also suppressed in a FoxO3a dependent manner in BCR-ABL-transformed cells, and FoxO3a-mediated regulation of BIM contributes to apoptosis induced by imatinib in BCR-ABL-transformed cell lines [169].…”

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

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FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

Jagani

Singh

Khosravi‐Far

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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Numerous studies have revealed that the BCR-ABL oncoprotein abnormally engages a multitude of signaling pathways, some of which may be important for its leukemogenic properties. Central to this has been the determination that the tyrosine kinase function of BCR-ABL is mainly responsible for its transforming potential, and can be targeted with small molecule inhibitors, such as imatinib mesylate (Gleevec, STI-571). Despite this apparent success, the development of clinical resistance to imatinib therapy, and the inability of imatinib to eradicate BCR-ABL-positive malignant hematopoietic progenitors demand detailed investigations of additional effector pathways that can be targeted for CML treatment. The promotion of cellular survival via the suppression of apoptotic pathways is a fundamental characteristic of tumor cells that enables resistance to anti-cancer therapies. As substrates of survival kinases such as Akt, the FoxO family of transcription factors, particularly FoxO3a, has emerged as playing an important role in the cell cycle arrest and apoptosis of hematopoietic cells. This review will discuss our current understanding of BCR-ABL signaling with a focus on apoptotic suppressive mechanisms and alternative approaches to CML therapy, as well as the potential for FoxO transcription factors as novel therapeutic targets.

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Section: Multiple Functions Of the Foxo Transcription Factors: A Focumentioning

confidence: 99%

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

Section: Multiple Functions Of the Foxo Transcription Factors: A Focumentioning

confidence: 99%

Section: Foxo Transcription Factors In Leukemiamentioning

confidence: 99%

See 3 more Smart Citations

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

Jagani

Singh

Khosravi‐Far

2008

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

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FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

et al. 2014

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Ineffective erythropoiesis is observed in many erythroid disorders including β-thalassemia and anemia of chronic disease in which increased production of erythroblasts that fail to mature exacerbate the underlying anemias. As loss of the transcription factor FOXO3 results in erythroblast abnormalities similar to the ones observed in ineffective erythropoiesis, we investigated the underlying mechanisms of the defective Foxo3−/− erythroblast cell cycle and maturation. Here we show that loss of Foxo3 results in overactivation of the JAK2/AKT/mTOR signaling pathway in primary bone marrow erythroblasts partly mediated by redox modulation. We further show that hyperactivation of mTOR signaling interferes with cell cycle progression in Foxo3 mutant erythroblasts. Importantly, inhibition of mTOR signaling, in vivo or in vitro enhances significantly Foxo3 mutant erythroid cell maturation. Similarly, in vivo inhibition of mTOR remarkably improves erythroid cell maturation and anemia in a model of β-thalassemia. Finally we show that FOXO3 and mTOR are likely part of a larger metabolic network in erythroblasts as together they control the expression of an array of metabolic genes some of which are implicated in erythroid disorders. These combined findings indicate that a metabolism-mediated regulatory network centered by FOXO3 and mTOR control the balanced production and maturation of erythroid cells. They also highlight physiological interactions between these proteins in regulating erythroblast energy. Our results indicate that alteration in the function of this network might be implicated in the pathogenesis of ineffective erythropoiesis.

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Sp1, acetylated histone‐3 and p300 regulate TRAIL transcription: Mechanisms of PDGF‐BB‐mediated VSMC proliferation and migration

Azahri

Bartolo

Khachigian

et al. 2012

J of Cellular Biochemistry

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We recently reported that TNF-related apoptosis-inducing ligand (TRAIL) is important in atherogenesis, since it can induce vascular smooth muscle cell (VSMC) proliferation and arterial thickening following injury. Here we show the first demonstrate that TRAIL siRNA reduces platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMC proliferation and migration. PDGF-BB-inducible VSMC proliferation was completely inhibited in VSMCs isolated from aortas of TRAIL(-/-) mice; whereas inducible migration was blocked compared to control VSMCs. TRAIL transcriptional control mediating this response is not established. TRAIL mRNA, protein and promoter activity was increased by PDGF-BB and subsequently inhibited by dominant-negative Sp1, suggesting that the transcription factor Sp1 plays a role. Sp1 bound multiple Sp1 sites on the TRAIL promoter, including two established (Sp1-1 and -2) and two novel Sp1-5/6 and -7 sites. PDGF-BB-inducible TRAIL promoter activity by Sp1 was mediated through these sites, since transverse mutations to each abolished inducible activity. PDGF-BB stimulation increased acetylation of histone-3 (ac-H3) and expression of the transcriptional co-activator p300, implicating chromatin remodelling. p300 overexpression increased TRAIL promoter activity, which was blocked by dominant-negative Sp1. Furthermore, PDGF-BB treatment increased the physical interaction of Sp1, p300 and ac-H3, while chromatin immunoprecipitation studies revealed Sp1, p300 and ac-H3 enrichment on the TRAIL promoter. Taken together, our studies demonstrate for the first time that PDGF-BB-induced TRAIL transcriptional activity requires the cooperation of Sp1, ac-H3 and p300, mediating increased expression of TRAIL which is important for VSMC proliferation and migration. Our findings have the promising potential for targeting TRAIL as a new therapeutic for vascular proliferative disorders.

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Cytokines and BCR-ABL mediate suppression of TRAIL-induced apoptosis through inhibition of forkhead FOXO3a transcription factor

Cited by 135 publications

References 40 publications

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

FoxO tumor suppressors and BCR–ABL-induced leukemia: A matter of evasion of apoptosis

FOXO3‐mTOR metabolic cooperation in the regulation of erythroid cell maturation and homeostasis

Sp1, acetylated histone‐3 and p300 regulate TRAIL transcription: Mechanisms of PDGF‐BB‐mediated VSMC proliferation and migration

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