Department of Biological Science, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
J Biol Chem. 2010 Apr 16;285(16):12232-40. doi: 10.1074/jbc.M109.065920. Epub 2010 Feb 17.
LXXLL/leucine zipper-containing alternative reading frame (ARF)-binding protein (LZAP) was recently shown to function as a tumor suppressor through inhibition of the NF-kappaB signaling pathway. LZAP is also known as a negative regulator of cell invasion, and its expression was demonstrated to be reduced in several tumor tissues. However, the molecular mechanism of the negative effect of LZAP on cell invasion is unclear. In this study, we identify NLBP as a novel LZAP-binding protein using tandem affinity purification. We demonstrate the negative effects of NLBP on cell invasion and the NF-kappaB signaling pathway. NLBP expression was not detected in hepatocellular carcinoma cells with strong invasive activity, whereas its expression was detected in a hepatocellular carcinoma cell line with no invasive activity. We also demonstrate that these two proteins mutually affect the stability of each other by inhibiting ubiquitination of the other protein. Based on these results, we suggest that NLBP may act as a novel tumor suppressor by inhibiting cell invasion, blocking NF-kappaB signaling, and increasing stability of the LZAP protein.
LXXLL/亮氨酸拉链结构域包含的另类读码框（ARF）结合蛋白（LZAP）最近被证明通过抑制 NF-κB 信号通路发挥肿瘤抑制作用。LZAP 也被称为细胞侵袭的负调节剂，其表达在几种肿瘤组织中降低。然而，LZAP 对细胞侵袭的负作用的分子机制尚不清楚。在这项研究中，我们使用串联亲和纯化鉴定 NLBP 作为 LZAP 的一种新型结合蛋白。我们证明了 NLBP 对细胞侵袭和 NF-κB 信号通路的负作用。在具有强侵袭活性的肝癌细胞中未检测到 NLBP 的表达，而在无侵袭活性的肝癌细胞系中检测到 NLBP 的表达。我们还证明这两种蛋白质通过抑制另一种蛋白质的泛素化来相互影响彼此的稳定性。基于这些结果，我们认为 NLBP 可能通过抑制细胞侵袭、阻断 NF-κB 信号通路和增加 LZAP 蛋白的稳定性来发挥新型肿瘤抑制作用。
