Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB
Control of oncogenesis and cancer therapy resistance by the transcription factor NF-κB
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DOI：
10.1172/jci11991
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发表时间：
2001-02-01
影响因子：
15.9
通讯作者：
Baldwin, AS
中科院分区：
文献类型：
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作者：
Baldwin, AS
Tax通过与IKK复合物直接相互作用激活NF-κB（12），并且Tax转化大鼠成纤维细胞需要激活NF-κB（13）。其他病毒转化蛋白，如EB病毒编码的（EBV编码的）蛋白、EBV蛋白核抗原2、潜伏膜蛋白1（LMP-1）、猿猴病毒40编码的大T和腺病毒编码的E1 A，均刺激NF-κB转录活性（14）。与该途径在转化和肿瘤发生中的作用一致，许多人实体瘤细胞系显示核NF-κB水平增加和/或NF-κ B依赖性报告基因表达增加。通过表达IκBα修饰形式（超阻遏物Iκ Bα）（15）或IKK显性负性形式（16）抑制NF-κB可阻断Ras诱导的病灶形成。由致癌融合蛋白BCR-ABL（可激活NF-κB）驱动的肿瘤发生也被超阻遏物IκBα阻断（17）。NF-κB在霍奇金淋巴瘤（18）（和多种转化细胞系）中被激活，抑制NF-κB可阻断这些淋巴瘤细胞的生长（18）。货车Waes及其同事（19）最近在头颈部鳞状细胞癌细胞中阻断NF-κB功能，并显示这抑制了异种移植物衍生的肿瘤生长。Sovak等人(20)报道NF-κB（p50-p65）的经典形式定位于乳腺癌细胞系和某些乳腺肿瘤的细胞核（20）。我们的观察结果一致认为，NF-κB似乎在乳腺癌中失调，但我们发现人类乳腺肿瘤显示核p52和Bcl-3沿着c-Rel的积累，而不是p65的持续激活（21）。推测Bcl-3通过与p52的相互作用促进转录活性。
Tax activates NF-κB through direct interactions with the IKK complex (12) and that activation of NF-κB is required for transformation of rat fibroblasts by Tax (13). Other viral transforming proteins, such as the Epstein-Barr virus–encoded (EBV-encoded) proteins, EBV protein nuclear antigen 2, the latent membrane protein 1 (LMP-1), the Simian virus-40–encoded Large-T, and adenovirus-encoded E1A, all stimulate NF-κB transcriptional activity (14). Consistent with a role for this pathway in transformation and tumorigenesis, many human solid tumor cell lines display increased nuclear NF-κB levels and/or increased NF-κB–dependent reporter expression.Further support for the involvement of NF-κB in oncogenesis comes from experiments in which the NF-κB pathway has been directly perturbed. Inhibition of NF-κB by expression of a modified form of IκBα (superrepressor IκBα)(15) or by a dominant negative form of IKK (16) blocks focus formation induced by Ras. Tumorigenesis driven by the oncogenic fusion protein BCR-ABL, which activates NF-κB, is also blocked by super-repressor IκBα (17). NF-κB is activated in Hodgkin’s lymphoma (18)(and in a variety of transformed cell lines), and inhibition of NF-κB blocks growth of these lymphoma cells (18). Van Waes and colleagues (19) recently blocked NF-κB function in head and neck squamous cell carcinoma cells and showed that this inhibited xenograftderived tumor growth. Sovak et al.(20) reported that the classic form of NF-κB (p50-p65) is localized to the nucleus in breast cancer cell lines and in some breast tumors (20). Our observations agree that NF-κB appears to be dysregulated in breast cancer, but we find that human breast tumors display an accumulation of nuclear p52 and Bcl-3 along with c-Rel, rather than consistent activation of p65 (21). Presumably Bcl-3 promotes transcriptional activity through interactions with p52.