KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation.
KiSS-1 represses 92-kDa type IV collagenase expression by down-regulating NF-kappa B binding to the promoter as a consequence of Ikappa Balpha -induced block of p65/p50 nuclear translocation.
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发表时间：
2001
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通讯作者：
C. Yan;H. Wang;D. Boyd
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作者：
C. Yan;H. Wang;D. Boyd
92-kDa IV型胶原酶（MMP-9）在组织重塑中起关键作用。我们进行了一项研究，以确定是否KiSS-1基因，以前显示抑制癌症扩散（转移），负调控MMP-9的表达。6株MMP-9 mRNA阳性细胞系KiSS-1 mRNA表达缺失。这些细胞系之一，HT-1080，稳定转染KiSS-1表达构建体，表现出显着较低的MMP-9酶活性/蛋白质和体外侵袭力。较低的MMP-9酶活性反映了稳态mRNA水平的降低，这反过来又是由于转录减弱。分别由佛波醇12-肉豆蔻酸酯13-乙酸酯和肿瘤坏死因子α激活ERK和JNK，导致MMP-9量增加，但KiSS-1表达不拮抗，表明调节MMP-9合成的MAPK途径不是KiSS-1的靶点。虽然MMP-9的表达受AP-1、Sp1和Ets转录因子的调节，但KiSS-1并不改变这些因子与MMP-9启动子的结合。然而，NF-κ B与MMP-9启动子的结合需要表达这种胶原酶，KiSS-1的表达减少。NF-κ B结合减少反映了KiSS-1转染细胞胞浆中IkappaB α水平增加导致细胞核中p50/p65减少。因此，KiSS-1通过降低NF-κ B与启动子的结合来减少MMP-9的表达。
The 92-kDa type IV collagenase (MMP-9) plays a critical role in tissue remodeling. We undertook a study to determine whether the KiSS-1 gene, previously shown to suppress cancer spread (metastases), negatively regulates MMP-9 expression. Six cell lines positive for MMP-9 mRNA were deficient in KiSS-1 mRNA. One of these cell lines, HT-1080, stably transfected with a KiSS-1 expression construct, demonstrated substantially lower MMP-9 enzyme activity/protein and in vitro invasiveness. The lower MMP-9 enzyme activity reflected reduced steady-state mRNA levels which, in turn, was due to attenuated transcription. Activation of ERKs and JNKs by phorbol 12-myristate 13-acetate and tumor necrosis factor alpha, respectively, leading to increased MMP-9 amounts was not antagonized by KiSS-1 expression, suggesting that MAPK pathways modulating MMP-9 synthesis are not the target of KiSS-1. Although MMP-9 expression is regulated by AP-1, Sp1, and Ets transcription factors, KiSS-1 did not alter the binding of these factors to the MMP-9 promoter. However, NF-kappaB binding to the MMP-9 promoter required for expression of this collagenase was reduced by KiSS-1 expression. Diminished NF-kappaB binding reflected less p50/p65 in the nucleus secondary to increased IkappaBalpha levels in the cytosols of the KiSS-1 transfectants. Thus, KiSS-1 diminishes MMP-9 expression by effecting reduced NF-kappaB binding to the promoter.