Schmidt Christian, Peng Bailu, Li Zhongkui, Sclabas Guido M, Fujioka Shuichi, Niu Jiangong, Schmidt-Supprian Marc, Evans Douglas B, Abbruzzese James L, Chiao Paul J
Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Mol Cell. 2003 Nov;12(5):1287-300. doi: 10.1016/s1097-2765(03)00390-3.
The transcription factor NF-kappaB regulates genes involved in innate and adaptive immune response, inflammation, apoptosis, and oncogenesis. Proinflammatory cytokines induce the activation of NF-kappaB in both transient and persistent phases. We investigated the mechanism for this biphasic NF-kappaB activation. Our results show that MEKK3 is essential in the regulation of rapid activation of NF-kappaB, whereas MEKK2 is important in controlling the delayed activation of NF-kappaB in response to stimulation with the cytokines TNF-alpha and IL-1alpha. MEKK3 is involved in the formation of the IkappaBalpha:NF-kappaB/IKK complex, whereas MEKK2 participates in assembling the IkappaBbeta:NF-kappaB/IKK complex; these two distinct complexes regulate the proinflammatory cytokine-induced biphasic NF-kappaB activation. Thus, our study reveals a novel mechanism in which different MAP3K and IkappaB isoforms are involved in specific complex formation with IKK and NF-kappaB for regulating the biphasic NF-kappaB activation. These findings provide further insight into the regulation of cytokine-induced specific and temporal gene expression.
转录因子核因子-κB调控参与固有免疫和适应性免疫反应、炎症、细胞凋亡及肿瘤发生的基因。促炎细胞因子在瞬时和持续阶段均可诱导核因子-κB的激活。我们研究了这种双相核因子-κB激活的机制。我们的结果表明，丝裂原活化蛋白激酶激酶3（MEKK3）在核因子-κB快速激活的调控中至关重要，而丝裂原活化蛋白激酶激酶2（MEKK2）在控制核因子-κB对细胞因子肿瘤坏死因子-α（TNF-α）和白细胞介素-1α（IL-1α）刺激的延迟激活中起重要作用。MEKK3参与κB抑制蛋白α（IkappaBalpha）:核因子-κB/IKK复合物的形成，而MEKK2参与κB抑制蛋白β（IkappaBbeta）:核因子-κB/IKK复合物的组装；这两种不同的复合物调控促炎细胞因子诱导的双相核因子-κB激活。因此，我们的研究揭示了一种新机制，即不同的丝裂原活化蛋白激酶激酶3（MAP3K）和κB抑制蛋白（IkappaB）异构体参与与IKK和核因子-κB形成特定复合物，以调控双相核因子-κB激活。这些发现为细胞因子诱导的特异性和时间性基因表达的调控提供了进一步的见解。
