Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells
Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells
复制标题
DOI：
10.1182/blood.v97.9.2798
复制
发表时间：
2001-05-01
期刊：
影响因子：
20.3
通讯作者：
Scheidereit, C
中科院分区：
文献类型：
--
作者：
Hinz, M;Löser, P;Scheidereit, C
组成型激活核因子 (NF)-kappaB 在多种肿瘤疾病中观察到，是霍奇金淋巴瘤中恶性霍奇金细胞和里德-斯滕伯格细胞 (H/RS) 的标志。鉴于组成型 NF-kappaB 对 H/RS 细胞活力的独特作用，通过使用超级阻遏蛋白 I kappaB DeltaN 的腺病毒表达来寻找 NF-kappaB 依赖性靶基因。鉴定出一组数量惊人但具有特征性的基因，包括细胞周期调节蛋白 cyclin D2、抗凋亡蛋白 Bfl-1/A1、c-IAP2、TRAF1 和 Bcl-x(L)，以及细胞表面受体 CD86 和 CD40。因此，组成型 NF-kappaB 活性维持基因网络的表达，这些基因在原代或培养的 H/RS 细胞中以频繁的标记样表达而闻名，有趣的是，能够通过 NF-kappaB 激活 CD86 或 Bcl-x(L) 的 CD40 本身是通过启动子近端结合位点受 NF-kappaB 转录调节的。 NF-kappaB 抑制导致大量自发且不依赖于 p53 的细胞凋亡，这可以通过 Bcl-x(L) 的异位表达来挽救，强调了其在 H/RS 细胞存活中的主导作用。因此，NF-kappaB 控制 H/RS 细胞中的信号网络，促进肿瘤细胞生长并赋予细胞凋亡抵抗力。 (Blood, 2001;97: 2798-2807) (C) 2001 年，美国血液学会。
Constitutively activated nuclear factor (NF)-kappaB is observed in a variety of neoplastic diseases and is a hallmark of the malignant Hodgkin and Reed-Sternberg cells (H/RS) in Hodgkin lymphoma. Given the distinctive role of constitutive NF-kappaB for H/RS cell viability, NF-kappaB-dependent target genes were searched for by using adenoviral expression of the super-repressor I kappaB DeltaN. A surprisingly small but characteristic set of genes, including the cell-cycle regulatory protein cyclin D2, the antiapoptotic proteins Bfl-1/A1, c-IAP2, TRAF1, and Bcl-x(L), and the cell surface receptors CD86 and CD40 were identified. Thus, constitutive NF-kappaB activity maintains expression of a network of genes, which are known for frequent, marker-like expression in primary or cultured H/RS cells, intriguingly, CD40, which is able to activate CD86 or Bcl-x(L) via NF-kappaB, is itself transcriptionally regulated by NF-kappaB through a promoter proximal binding site. NF-kappaB inhibition resulted in massive spontaneous and p53-independent apoptosis, which could be rescued by ectopic expression of Bcl-x(L), underscoring its dominant role in survival of H/RS cells. Hence, NF-kappaB controls a signaling network in H/RS cells, which promotes tumor cell growth and confers resistance to apoptosis. (Blood, 2001;97: 2798-2807) (C) 2001 by The American Society of Hematology.