Distinct promoters mediate constitutive and inducible Bcl-XL expression in malignant lymphocytes

Habens, Fay; Lapham, Abigail; Dallman, Claire L.; Pickering, Becky M.; Michels, Jorg; Marcusson, Eric G.; Johnson, Peter; Packham, Graham

doi:10.1038/sj.onc.1209979

Cited by 13 publications

(15 citation statements)

References 49 publications

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“…(Top) The distal (IB) and proximal (IA) non-coding exons, and part of the first coding exon (II) including the translational start site (ATG). Additionally, the three described BCL2L1 promoters (p1B, p1A, p2) are depicted [ 17 ]. (Bottom) Major BCL2L1 transcripts starting from promoter p1B or p1A, comprising exon IB or IA, respectively, or starting upstream from exon II.…”

Section: Resultsmentioning

confidence: 99%

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

Keitel

Scheel²,

Thomale

et al. 2014

Oncotarget

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The transition from an epithelial to a mesenchymal phenotype (EMT) confers increased invasiveness and clonogenic potential to tumor cells. We used a breast epithelium-derived cell culture model to evaluate the impact of EMT on the cellular sensitivity towards chemotherapeutics and apoptotic stimuli. Cells that had passed through an EMT acquired resistance towards chemotherapeutics and death ligands. Mechanistically, we found that the levels of the apoptosis inhibitor Bcl-xL were strongly enhanced in mesenchymal versus epithelial cells, whereas the pro-apoptotic proteins Bim and Puma were diminished. Clinical samples from breast cancer showed enhanced Bcl-xL staining in cells that had dispersed into the desmoplastic stroma, as compared to cells that were part of large tumor cell aggregates, suggesting increased Bcl-xL expression when cells invade the stroma. Bcl-xL was necessary for apoptotic resistance in mesenchymal cells, and its expression was sufficient to confer such resistance to epithelial cells. To antagonize Bcl-xL, BH3-mimetics were used. They successfully interfered with the proliferation and survival of mesenchymal cells, and also inhibited the growth of xenograft tumors raised from the mesenchymal subpopulation. We conclude that enhanced Bcl-xL levels confer resistance to cells upon EMT, and that Bcl-xL represents a promising target for therapy directed against invasive cancer cells.

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Section: Resultsmentioning

confidence: 99%

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

Keitel

Scheel²,

Thomale

et al. 2014

Oncotarget

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“…1), we asked whether such up-regulation was at the mRNA level. The bcl-X gene contains multiple promoters, and its transcription may generate several splice variants [40–42]. The main Bcl-xL transcript is termed in the rat “transcript variant 3” and codes for protein isoform 2 with molecular mass of approximately 26 kDa.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, we found an increase in the pancreatic level of not only the main transcript but also an alternative splice variant from the bcl-X gene. Transcriptional regulation of this gene [40–42] has not been studied in pancreatitis. One regulator of Bcl-xL gene expression in a number of cell types is the transcription factor NF-κB [41].…”

Section: Discussionmentioning

confidence: 99%

Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis

Sung

Odinokova

Mareninova

et al. 2009

Experimental Cell Research

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Acinar cells in pancreatitis die through apoptosis and necrosis, the roles of which are different. The severity of experimental pancreatitis correlates directly with the extent of necrosis and inversely, with apoptosis. Apoptosis is mediated by the release of cytochrome c into the cytosol followed by caspase activation, whereas necrosis is associated with the mitochondrial membrane potential (ΔΨm) loss leading to ATP depletion. Here, we investigate the role of Bcl-2 proteins in apoptosis and necrosis in pancreatitis. We found up-regulation of prosurvival Bcl-2 proteins in pancreas in various experimental models of acute pancreatitis, most pronounced for Bcl-xL. This up-regulation translated into increased levels of Bcl-xL and Bcl-2 in pancreatic mitochondria. Bcl-xL/Bcl-2 inhibitors induced ΔΨm loss and cytochrome c release in isolated mitochondria. Corroborating the results on mitochondria, Bcl-xL/Bcl-2 inhibitors induced ΔΨm loss, ATP depletion and necrosis in pancreatic acinar cells, both untreated and hyperstimulated with CCK-8 (in vitro pancreatitis model). Together Bcl-xL/Bcl-2 inhibitors and CCK induced more necrosis than either treatment alone. Bcl-xL/Bcl-2 inhibitors also stimulated cytochrome c release in acinar cells leading to caspase-3 activation and apoptosis. However, different from their effect on pronecrotic signals, the stimulation by Bcl-xL/Bcl-2 inhibitors of apoptotic responses was less in CCK-treated than control cells. Therefore, Bcl-xL/Bcl-2 inhibitors potentiated CCK-induced necrosis but not apoptosis. Correspondingly, transfection with Bcl-xL siRNA stimulated necrosis but not apoptosis in the in vitro pancreatitis model. Further, in animal models of pancreatitis Bcl-xL up-regulation inversely correlated with necrosis, but not apoptosis. Results indicate that Bcl-xL and Bcl-2 protect acinar cells from necrosis in pancreatitis by stabilizing mitochondria against death signals. We conclude that Bcl-xL/Bcl-2 inhibition would aggravate acute pancreatitis, whereas Bcl-xL/Bcl-2 up-regulation presents a strategy to prevent or attenuate necrosis in pancreatitis.

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“…The Bcl-X promoter region is complex because it contains different promoters that generate different 5Ј noncoding exons and different proportions of Bcl-X L and Bcl-X S mRNAs (15)(16)(17)(18). It has been previously demonstrated that various nuclear factors including NFB, STAT, Ets, Ikaros, and steroid hormones activate Bcl-X transcription acting on its different promoters in various cell types (15, 17, 18, 26 -28).…”

Section: Discussionmentioning

confidence: 99%

Growth Factor Stimulation Induces Cell Survival by c-Jun·ATF2-dependent Activation of Bcl-XL

Salameh¹,

Galvagni²,

Anselmi

et al. 2010

Journal of Biological Chemistry

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Growth factor stimulation induces c-Jun-dependent survival of primary endothelial cells. However, the mechanism of c-Jun anti-apoptotic activity has not been identified. We here demonstrate that in response to growth factor treatment, primary human endothelial cells as well as mouse fibroblasts respond with an increased expression of c-Jun that forms a complex with ATF2. This complex activates the expression of the anti-apoptotic protein Bcl-X L . By site-directed mutagenesis experiments, we identified two AP-1-binding sites located within the proximal promoter of the Bcl-X gene. Site-directed mutagenesis demonstrated that these AP-1 sites are required for the transcriptional activation of the promoter. Chromatin immunoprecipitation experiments show that in response to growth factor treatment, the heterodimer c-Jun⅐ATF2 binds to these functional AP-1 sites. Silencing of either c-Jun or ATF2 demonstrated that both nuclear factors are required for the activation of the proximal Bcl-X promoter. Taken together, our experiments provide evidence that growth factor-independent signaling pathways converge in the formation of an active c-Jun⅐AFT2 dimer, which induces the expression of the anti-apoptotic factor Bcl-X L that mediates a pro-survival response.

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Distinct promoters mediate constitutive and inducible Bcl-XL expression in malignant lymphocytes

Cited by 13 publications

References 49 publications

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

Bcl-xL mediates therapeutic resistance of a mesenchymal breast cancer cell subpopulation

Prosurvival Bcl-2 proteins stabilize pancreatic mitochondria and protect against necrosis in experimental pancreatitis

Growth Factor Stimulation Induces Cell Survival by c-Jun·ATF2-dependent Activation of Bcl-XL

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