Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

Essafi, Abdelkader; Mattos, Silvia Fernández de; Hassen, Yasmin; Soeiro, Inês; Mufti, Ghulam J.; Thomas, N. Shaun B.; Medema, René H.; Lam, Eric W.‐F.

doi:10.1038/sj.onc.1208421

Cited by 264 publications

(251 citation statements)

References 49 publications

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“…Two of its known targets implicated in apoptosis are Fas ligand [25] and Bim [21][22][23]. FOXO3a directly binds to the Bim promoter and activates Bim transcription.…”

Section: Discussionmentioning

confidence: 99%

“…The Bim promoter contains two putative FOXO3a binding sites and FOXO3a has been implicated in regulating Bim expression in several other cell types [21][22][23]. Furthermore, other members of the MAP kinase family, such as JNK and ERK5, have been reported to directly or indirectly regulate FOXO3a expression [28,29].…”

Section: Foxo3a Mediates Sodium Arsenite-induced Bim Expressionmentioning

confidence: 99%

“…The Bim promoter contains two putative binding sites for FOXO3a, a forkhead family transcription factor. Furthermore, FOXO3a can directly activate the Bim promoter and has been implicated in several forms of apoptosis [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

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p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Cai

Xia

2008

Apoptosis

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Sodium arsenite induces apoptosis in PC12 cells by activating the stress-activated p38 MAP kinase and the pro-apoptotic Bcl-2 family protein Bim EL . However, the relationship between p38 and Bim EL in this apoptosis has not been fully defined. Here, we report that sodium arsenite stimulates the protein expression and promoter activity of Bim EL in a p38-dependent manner. Sodium arsenite also caused nuclear translocation of FOXO3a, indicative of FOXO3a activation. Addition of a p38 inhibitor prevented FOXO3a nuclear translocation. RNAi knock down of FOXO3a inhibited Bim promoter activity, Bim EL protein expression, and arsenite-induced apoptosis. Our data identify p38 activation of FOXO3a and subsequent induction of Bim EL expression as a novel apoptotic mechanism. Together with our previous finding that Bim EL is phosphorylated and activated by p38, these results demonstrate that p38 induces apoptosis by regulating Bim EL at both the transcriptional and post-translational levels.

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“…Two of its known targets implicated in apoptosis are Fas ligand [25] and Bim [21][22][23]. FOXO3a directly binds to the Bim promoter and activates Bim transcription.…”

Section: Discussionmentioning

confidence: 99%

Section: Foxo3a Mediates Sodium Arsenite-induced Bim Expressionmentioning

confidence: 99%

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p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Cai

Xia

2008

Apoptosis

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“…Our study supports this premise, as we were able to markedly increase the killing of transcriptional activator of bim. 31 Loss of ERK1/2 or AKT kinase activity is probably responsible for de-phosphorylation and activation of Bim and Bad, respectively. 32 induces Bmf and Bik approximately 30-fold more potently than imatinib, but how this is achieved is presently unknown.…”

Section: Discussionmentioning

confidence: 99%

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

et al. 2007

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Bcr-Abl is the cause of Philadelphia-positive (Ph þ ) leukemias and also constitutes their principal therapeutic target, as exemplified by dramatic effects of imatinib mesylate. However, mono-targeting of Bcr-Abl does not always achieve complete leukemia eradication, and additional strategies those enable complete elimination of leukemic cells are desired to develop. Here we demonstrate that INNO-406, a much more active Bcr-Abl tyrosine kinase inhibitor than imatinib, augments the activities of several proapoptotic Bcl-2 homology (BH)3-only proteins (Bim, Bad, Bmf and Bik) and induces apoptosis in Ph þ leukemia cells via Bcl-2 family-regulated intrinsic apoptosis pathway. ABT-737, an inhibitor of antiapoptotic Bcl-2 and Bcl-X L , greatly enhanced the apoptosis by INNO-406, even in INNO-406-less sensitive cells with Bcr-Abl point mutations except T315I mutation. In contrast, co-treatment with INNO-406 and other pharmacologic inducers of those BH3-only proteins, such as 17-allylaminogeldanamycin, an heat shock protein-90 inhibitor, or PS-341, a proteasome inhibitor, did not further increase the BH3-only protein levels or sensitize leukemic cells to INNO-406-induced apoptosis, suggesting a limit to how much expression levels of BH3-only proteins can be increased by anticancer agents. Thus, double-barrelled molecular targeting for Bcr-Abl-driven oncogenic signaling and the cell protection by antiapoptotic Bcl-2 family proteins may be the rational therapeutic approach for eradicating Ph þ leukemic cells.

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“…In leukaemia, FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through a STAT5 element in the cyclin D2 promoter (Essafi et al, 2005).…”

Section: Basic Mechanismsmentioning

confidence: 99%

Drug resistance in cancer

Yagüe

Raguz

2005

Br J Cancer

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Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission tomography to study anticancer-drug resistance. The progress made in translating these findings to the clinic, like Gefitinib, P-glycoprotein phenotyping, or genome-wide analysis technology, was also discussed. BASIC MECHANISMSIt has been now widely demonstrated that normal primary cells become tumorigenic when expressing hTERT, SV40 proteins LT and ST, and oncogenic ras. We are using the step-wise model of tumorigenesis (Hahn and Weinberg, 2002) to determine whether the ability of human primary embryonic skin fibroblasts to develop drug resistance is exclusive to the transformed state or extends to premalignant cells. Interestingly, cells at early stages of the tumorigenesis process were able to develop doxorubicinresistant derivatives. This demonstrates that, at least in this cell model system, the ability to acquire drug resistance is not a consequence of the accumulation of mutations that occur during the proliferation of a transformed cell, but it is an intrinsic characteristic that appears before the complete set of genetic transforming alterations. We are currently dissecting the minimal set of genetic alterations necessary to switch on the ability to acquire drug resistance, and dissecting the drug resistance signatures by microarray analysis.Drugs that produce DNA interstrand crosslinks between the two complementary strands of the double helix, are among the most widely used and most effective anticancer agents. Victoria Spanswick (London) described a highly sensitive and robust method to determine DNA crosslinks in leukaemia, myeloma and solid tumour samples: the single-cell gel electrophoresis (Comet) assay. Cells isolated from melphalan-treated multiple myeloma patients showed between 42 and 100% repair of radiation-induced DNA crosslinks, whereas no repair was observed in cells from naive patients. These findings suggest that DNA interstrand crosslink repair may be an important mechanism of clinical resistance to melphalan in multiple myeloma (Spanswick et al, 2002). Spanswick and co-workers are currently determining whether molecules involved in the nucleotide excision repair and double-strand break repair pathways are implicated in this process.The cytochrome P450 enzymes are a large family of constitutive and inducible haem-containing oxidative enzymes with roles in the metabolism of xenobiotics and steroid hormone synthesis. Georgia Pass (Dundee) described the use of a mouse model with a conditional deletion in the liver cytochrome P450 reductase (HRN) to study cyclophosphamide (CPA) toxicokinetics and therapeutic response. CPA is an anticancer prodrug that is dependent on cytoc...

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Direct transcriptional regulation of Bim by FoxO3a mediates STI571-induced apoptosis in Bcr-Abl-expressing cells

Cited by 264 publications

References 49 publications

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

p38 MAP kinase mediates arsenite-induced apoptosis through FOXO3a activation and induction of Bim transcription

Apoptosis-based dual molecular targeting by INNO-406, a second-generation Bcr-Abl inhibitor, and ABT-737, an inhibitor of antiapoptotic Bcl-2 proteins, against Bcr-Abl-positive leukemia

Drug resistance in cancer

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