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. 1999 Feb 15;13(4):382-7.
doi: 10.1101/gad.13.4.382.

The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis

W X Zong  1 , L C Edelstein, C Chen, J Bash, C Gélinas
Affiliations

"V体育2025版" The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis

W X Zong et al. Genes Dev. .

Abstract

Bcl-2-family proteins are key regulators of the apoptotic response VSports手机版. Here, we demonstrate that the pro-survival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB. We show that bfl-1 gene expression is dependent on NF-kappaB activity and that it can substitute for NF-kappaB to suppress TNFalpha-induced apoptosis. bfl-1 promoter analysis identified an NF-kappaB site responsible for its Rel/NF-kappaB-dependent induction. The expression of bfl-1 in immune tissues supports the protective role of NF-kappaB in the immune system. The activation of Bfl-1 may be the means by which NF-kappaB functions in oncogenesis and promotes cell resistance to anti-cancer therapy. .

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"VSports" Figures

Figure 1
Figure 1
bfl-1 gene expression is activated by c-Rel and RelA but not by p50/NF-κB1. (a) Expression of bfl-1 transcripts in HtTA–CCR43 cells maintained in the presence (lane 1) or absence of tetracycline for 12, 24, 36, or 48 hr to induce c-rel expression (lanes 2–5). The blot was successively hybridized to 32P-labeled probes for bfl-1, iκbα, c-rel, and gapdh. (b) bfl-1 gene expression in HtTA–p50 and HtTA–RelA cells maintained in the presence (lanes 1,4) or absence of tetracycline for 24 or 48 hr to induce the expression of p50 or relA (lanes 2,3,5,6). The blot was hybridized to bfl-1 and actin probes.
Figure 2
Figure 2
The expression of bfl-1 is dependent on endogenous Rel/NF-κB activity. (a) The activation of NF-κB induces bfl-1 gene expression. Human HT1080 cells untreated or treated with TNFα (lanes 1,2), human Jurkat T cells treated with DMSO as a control (lane 3) or with PMA plus ionomycin (lane 4), mouse 70Z/3 pre-B cells untreated or treated with LPS (lanes 5,6), mouse WEHI-231 B cells untreated or treated with TNFα (lanes 7,8), LPS (lanes 9,10), or PMA (lanes 11,12). Total RNA (20 μg) was hybridized to bfl-1 and actin probes. (b) The induction of bfl-1 gene expression is repressed by a dominant IκBαΔN inhibitor. Jurkat T cells expressing wild-type IκBα or an IκBαΔN transgene were treated with DMSO alone (lanes 1,3) or with PMA plus ionomycin (lanes 2,4). Total RNA (20 μg) was hybridized to 32P-labeled probes for bfl-1, il-8, and 28S rRNA.
Figure 2
Figure 2
The expression of bfl-1 is dependent on endogenous Rel/NF-κB activity. (a) The activation of NF-κB induces bfl-1 gene expression. Human HT1080 cells untreated or treated with TNFα (lanes 1,2), human Jurkat T cells treated with DMSO as a control (lane 3) or with PMA plus ionomycin (lane 4), mouse 70Z/3 pre-B cells untreated or treated with LPS (lanes 5,6), mouse WEHI-231 B cells untreated or treated with TNFα (lanes 7,8), LPS (lanes 9,10), or PMA (lanes 11,12). Total RNA (20 μg) was hybridized to bfl-1 and actin probes. (b) The induction of bfl-1 gene expression is repressed by a dominant IκBαΔN inhibitor. Jurkat T cells expressing wild-type IκBα or an IκBαΔN transgene were treated with DMSO alone (lanes 1,3) or with PMA plus ionomycin (lanes 2,4). Total RNA (20 μg) was hybridized to 32P-labeled probes for bfl-1, il-8, and 28S rRNA.
Figure 3
Figure 3
bfl-1 is highly expressed in human immune tissues and correlates with endogenous Rel/NF-κB activity. Multiple tissue Northern blots (Clontech) human II (lanes 1–5) and human immune system II (lanes 6–11) were successively hybridized to 32P-labeled probes for bfl-1, iκbα, c-rel, relA, and actin.
Figure 4
Figure 4
Bfl-1 suppresses TNFα-induced cell death. (a) HeLa cells were cotransfected with pCMV–β-gal, together with an empty pCMV vector or pCMV–bfl-1. The cells were treated with CHX alone or together with TNFα for 16 hr, stained with X-gal, and photographed. (b) Quantitation of cell survival upon expression of bfl-1. The viability of HeLa, HtTA-1, and HT1080 cells transfected as described in a represents the ratio of cells expressing β–gal in wells treated with TNFα plus CHX over that in wells treated with CHX alone. Cells from a minimum of 10 randomly chosen fields were counted. The average survival from three independent experiments is shown. (c) HeLa cells were cotransfected with pCMV-β-gal and an empty pCMV vector or pCMV–IκBαM, alone or together with pCMV-bfl-1. The cells were treated with TNFα alone for 16 hr and stained with X-gal. Cell survival represents the ratio of cells expressing β-gal in wells treated with TNFα over that in wells left untreated. The average survival from three experiments is shown.
Figure 5
Figure 5
The human bfl-1 promoter contains a consensus NF-κB site responsible for its Rel-dependent induction. (a) Schematic representation of CAT reporter gene constructs driven by various regions of the human bfl-1 promoter. (b) c-Rel-dependent transactivation of the bfl-1 promoter. HtTA-1 cells were cotransfected with bfl-1–CAT reporter plasmids together with pCMV–c-rel or an empty pCMV vector as a control. The IL6κBCAT plasmid containing three NF-κB DNA sites derived from the IL6 promoter was used as a positive control. The average CAT activity from three independent experiments is shown. (c) TNFα-inducible activation of the bfl-1 promoter. HtTA-1 cells were transfected with −1374/+81 bfl-1–CAT or the control IL6κBCAT reporter plasmid. Where indicated, cells were stimulated with TNFα for 6 hr prior to harvest. The average fold activation from three independent experiments is shown. (d) κB site-dependent activation of the bfl-1 promoter. Cells were cotransfected with wild-type −1374/+81 bfl-1–CAT or the mutant −1374/+81mκB–CAT reporter plasmid, with a mutated NF-κB site at position −833 (GTTTATTTACC), together with pCMV–c-rel or an empty CMV vector as a control. IL6κBCAT was used as a control.
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VSports注册入口 - References

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