Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma.
Bcl3 regulates pro-survival and pro-inflammatory gene expression in cutaneous T-cell lymphoma.
复制标题
DOI：
10.1016/j.bbamcr.2014.07.012
复制
发表时间：
2014-11
影响因子：
5.1
通讯作者：
Vancurova, Ivana
中科院分区：
文献类型：
--
作者：
Chang, Tzu-Pei;Vancurova, Ivana
皮肤T细胞淋巴瘤（CTCL）的晚期特征不仅在于促炎细胞因子水平降低，导致对感染的高度易感性，而且在于NFκB的高组成性活性，其促进细胞存活和抗凋亡。IκB家族原癌基因Bcl 3的高表达与人类不同类型肿瘤的发病机制有关，但Bcl 3在CTCL中的作用及调控尚未见报道。在这里，我们表明，Bcl 3是高度表达CTCL Hut-78和HH细胞。Bcl 3水平的抑制降低了促存活基因cIAP 1和cIAP 2的表达，降低了细胞活力，并增加了CTCL凋亡。有趣的是，Bcl 3抑制伴随着CTCL细胞中促炎细胞因子IL-8和IL-17的表达和释放增加。染色质免疫沉淀研究表明，Bcl 3通过直接结合其启动子来调节cIAP 1、cIAP 2、IL-8和IL-17基因的表达。Bcl 3的表达受硼替佐米（BZ）介导的蛋白酶体抑制的调节，BZ抑制Bcl 3向其靶启动子的募集，导致cIAP 1和cIAP 2的表达降低，但IL-8和IL-17的表达增加。Bcl 3的表达是通过Bcl 3启动子上的NFκB亚基交换来调节的。在未处理的细胞中，Bcl 3启动子主要被p65/p50异二聚体占据，诱导Bcl 3表达;然而，在BZ处理的细胞中，p65/50异二聚体被p52亚基取代，导致Bcl 3转录抑制。这些数据提供了对Bcl 3在CTCL中的功能和调节的第一个见解，并表明Bcl 3在这些细胞中具有重要的促存活和免疫抑制作用。
The advanced stages of cutaneous T cell lymphoma (CTCL) are characterized not only by decreased levels of pro-inflammatory cytokines, resulting in high susceptibility to infections, but also by high constitutive activity of NFκB, which promotes cell survival and resistance to apoptosis. The increased expression of the proto-oncogene Bcl3 belonging to IκB family is associated with the pathogenesis of the different types of human cancer, yet, the function and regulation of Bcl3 in CTCL have not been studied. Here, we show that Bcl3 is highly expressed in CTCL Hut-78 and HH cells. The suppression of Bcl3 levels decreases the expression of the pro-survival genes cIAP1 and cIAP2, reduces cell viability, and increases CTCL apoptosis. Interestingly, Bcl3 suppression concomitantly increases expression and the release of the pro-inflammatory cytokines IL-8 and IL-17 in CTCL cells. Chromatin immunoprecipitation studies show that Bcl3 regulates cIAP1, cIAP2, IL-8 and IL-17 gene expression through direct binding to their promoters. Bcl3 expression is regulated by bortezomib (BZ)-mediated proteasome inhibition, and BZ inhibits Bcl3 recruitment to its target promoters, resulting in decreased expression of cIAP1 and cIAP2, but increased expression of IL-8 and IL-17. The Bcl3 expression is regulated through NFκB subunit exchange on Bcl3 promoter. In untreated cells, the Bcl3 promoter is occupied predominantly by p65/p50 heterodimers, inducing Bcl3 expression; however, in BZ-treated cells, the p65/50 heterodimers are replaced by p52 subunits, resulting in Bcl3 transcriptional repression. These data provide the first insights into the function and regulation of Bcl3 in CTCL, and indicate that Bcl3 has an important pro-survival and immunosuppressive role in these cells.
登录
查看更多内容
影响因子：
28.5
作者：
Jain S;Zain J;O'Connor O
通讯作者：
O'Connor O
来自恶性细胞的Th2细胞因子抑制了Th1反应并在白血病皮肤T细胞淋巴瘤中抑制全球Th2偏置。
DOI：
10.1158/1078-0432.ccr-12-3488
发表时间：
2013-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Guenova E;Watanabe R;Teague JE;Desimone JA;Jiang Y;Dowlatshahi M;Schlapbach C;Schaekel K;Rook AH;Tawa M;Fisher DC;Kupper TS;Clark RA
通讯作者：
Clark RA
影响因子：
10.3
作者：
Biskup, E.;Kamstrup, M. R.;Gniadecki, R.
通讯作者：
Gniadecki, R.
影响因子：
2.4
作者：
Adams, J;Kauffman, M
通讯作者：
Kauffman, M
影响因子：
20.3
作者：
Berger, CL;Tigelaar, R;Edelson, RL
通讯作者：
Edelson, RL