Habens F, Lapham A S, Dallman C L, Pickering B M, Michels J, Marcusson E G, Johnson P W M, Packham G
Cancer Research UK Clinical Centre, Cancer Sciences Division, University of Southampton School of Medicine, Southampton General Hospital, Southampton, UK.
Oncogene. 2007 Mar 22;26(13):1910-9. doi: 10.1038/sj.onc.1209979. Epub 2006 Sep 18.
Bcl-X(L) is a Bcl-2-related survival protein that is essential for normal development. Bcl-X(L) expression is rapidly induced by a wide range of survival signals and many cancer cells constitutively express high levels. The Bcl-X gene has a complex organization with multiple promoters giving rise to RNAs with alternate 5' non-coding exons. Here we have investigated the mechanisms that control basal and induced expression of Bcl-X(L) in B-lymphoma cells. Antisense experiments demonstrated that Bcl-X(L) was essential for survival of Akata6 B-lymphoma cells. The levels of RNAs containing the IB Bcl-X non-coding exon, derived from the distal 1B promoter, correlated with basal expression of Bcl-X(L) in primary malignant B cells and this promoter was highly active in B-cell lines. The activity of this promoter was largely dependent on a single Ets binding site and Ets family proteins were bound at this promoter in intact cells. CD40 ligand (CD40L)-induced cell survival was associated with increased Bcl-X(L) expression and accumulation of exon IA-containing RNAs, derived from the proximal 1A promoter. Nuclear factor-kappaB (NF-kappaB) inhibition prevented induction of Bcl-X(L) protein and exon IA-containing RNAs by CD40L. Therefore, the distal Bcl-X 1B promoter plays a critical role in driving constitutive expression-mediated via Ets family proteins in malignant B cells, whereas NF-kappaB plays a central role in the induction of Bcl-X(L) in response to CD40 signalling via the proximal 1A promoter.
Bcl-X(L)是一种与Bcl-2相关的生存蛋白，对正常发育至关重要。Bcl-X(L)的表达可被多种生存信号迅速诱导，许多癌细胞持续高水平表达。Bcl-X基因结构复杂，有多个启动子，可产生具有不同5'非编码外显子的RNA。在此，我们研究了控制Bcl-X(L)在B淋巴瘤细胞中基础表达和诱导表达的机制。反义实验表明，Bcl-X(L)对Akata6 B淋巴瘤细胞的存活至关重要。源自远端1B启动子的含有IB Bcl-X非编码外显子的RNA水平，与原发性恶性B细胞中Bcl-X(L)的基础表达相关，且该启动子在B细胞系中高度活跃。该启动子的活性很大程度上依赖于单个Ets结合位点，在完整细胞中Ets家族蛋白结合于该启动子。CD40配体（CD40L）诱导的细胞存活与Bcl-X(L)表达增加以及源自近端1A启动子的含外显子IA的RNA积累有关。核因子-κB（NF-κB）抑制可阻止CD40L诱导Bcl-X(L)蛋白和含外显子IA的RNA。因此，远端Bcl-X 1B启动子在驱动恶性B细胞中由Ets家族蛋白介导的组成型表达方面起关键作用，而NF-κB在通过近端1A启动子响应CD40信号诱导Bcl-X(L)方面起核心作用。
