Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2
Gadd45β mediates the NF-κB suppression of JNK signalling by targeting MKK7/JNKK2
复制标题
DOI：
10.1038/ncb1093
复制
发表时间：
2004-02-01
影响因子：
21.3
通讯作者：
Franzoso, G
中科院分区：
文献类型：
--
作者：
Papa, S;Zazzeroni, F;Franzoso, G
NF-kappaB/Rel 转录因子控制细胞凋亡，也称为程序性细胞死亡。这种控制对于肿瘤发生、癌症化疗耐药性以及拮抗肿瘤坏死因子 α (TNFalpha) 诱导的杀伤作用至关重要(1,2)。对于 TNFα，NF-kappaB 的抗凋亡活性涉及抑制 c-Jun N 末端激酶 (JNK) 级联 (3-5)。通过无偏筛选，我们之前已鉴定出 Gadd45beta/Myd118（诱导因子 Gadd45 家族的成员）(6)，是 NF-kappaB 抑制活性的关键介质(3)。然而，Gadd45 抑制 JNK 信号传导的机制尚不清楚。在这里，我们将 MKK7/JNKK2（JNK(7,8) 的一种特定且必需的激活剂）确定为 Gadd45beta 的靶标，事实上，也是 NF-kappaB 本身的靶标。 Gadd45beta 直接结合 MKK7 并阻断其催化活性，从而提供 NF-kappaB 和 JNK 途径之间的分子联系。重要的是，Gadd45 需要拮抗 TNFα 诱导的细胞毒性，而破坏 Gadd45beta/MKK7 相互作用的肽会阻碍 Gadd45beta 以及 NF-κB 抑制这种细胞毒性的能力。这些发现为 NF-kappaB 控制 JNK 激活奠定了基础，并将 MKK7 确定为抗炎和抗癌治疗的潜在靶点。
NF-kappaB/Rel transcription factors control apoptosis, also known as programmed cell death. This control is crucial for oncogenesis, cancer chemo-resistance and for antagonizing tumour necrosis factor alpha (TNFalpha)- induced killing(1,2). With regard to TNFalpha, the anti-apoptotic activity of NF-kappaB involves suppression of the c-Jun N-terminal kinase (JNK) cascade(3-5). Using an unbiased screen, we have previously identified Gadd45beta/Myd118, a member of the Gadd45 family of inducible factors(6), as a pivotal mediator of this suppressive activity of NF-kappaB(3). However, the mechanisms by which Gadd45 inhibits JNK signalling are not understood. Here, we identify MKK7/JNKK2 - a specific and essential activator of JNK(7,8) - as a target of Gadd45beta, and in fact, of NF-kappaB itself. Gadd45beta binds to MKK7 directly and blocks its catalytic activity, thereby providing a molecular link between the NF-kappaB and JNK pathways. Importantly, Gadd45 is required to antagonize TNFalpha-induced cytotoxicity, and peptides disrupting the Gadd45beta/MKK7 interaction hinder the ability of Gadd45beta, as well as of NF-kappaB, to suppress this cytotoxicity. These findings establish a basis for the NF-kappaB control of JNK activation and identify MKK7 as a potential target for antiinflammatory and anti-cancer therapy.