Novel roles of IKK complex to program gene expression

NF-KappaB诱导的IKK信号体复合物是一系列细胞外应激样和炎症反应刺激的最终接受者和集成者。IKK复合体由两个丝氨酸苏氨酸激酶（IKKalpha和IKKbeta）和一个共催化调节/对接蛋白（NEMO/IKKy）组成。IKK(3和NEMO/IKKgamma是诱导NF-KB核易位和DNA结合活性以响应TNFalpha和IL-1等炎症反应介质所必需的，而IKKalpha在很大程度上被认为是由这些刺激激活NF-KappaB所必需的。令人惊讶的是，我们最近发现IKKalpha对于诱导

The NF-KappaB inducing IKK signalsome complex is the final receiver and integrator of a host of extracellular stress-like and inflammatory response stimuli. The IKK complex consists of two serinelthreonine kinases (IKKalpha and IKKbeta) and a con-catalytic regulatory/docking protein (NEMO/IKKy). IKK(3 and NEMO/IKKgamma are essential for inducing NF-KB nuclear translocation and DNA binding activity in response to mediators of inflammatory responses like TNFalpha and IL-1, while IKKalpha is largely believed to be dispensible for activating NF-KappaB by these stimuli. Surprisingly, we have recently found that IKKalpha is essential for inducing the transcriptional competence of nuclear NF-KappaB subunits in response to inflammatory cytokines, implying that it plays a critical role in activating NF-KB independent of its DNA binding activity. Consequently, one aim of this proposal will be to elaborate the molecular requirements and mechanisms of action of IKKalpha as a co-global mediator (along with IKKbeta and NEMO/IKKgamma) of stress-like responses culminating in NF-kappaB activation. We have also discovered that the IKK signalsome simultaneously co-ordinates the global induction and repression of cellular gene expression. In a second aim we will elaborate the mechanisms of action of the IKK signalsome as a mediator of NF-KappaB dependent gene repression. We have hypothesized that IKK mediated NF-KappaB activation operates like a co-ordinately controlled on/off switch that alters physiological responses in vivo. Interestingly a subset of the genes, which are repressed in response to extracellular stimulus dependent and IKK mediated NF-KB activation, are also induced targets of the E2F-I. E2F-1 is capable of inducing cell cycle arrest, apoptosis and cell cycle progression depending on its degree of activation and the physiological state of the cell. Experimental conditions in primary and established cells will be established, which lead to interference between NF-KB and E2F on specific genomic targets. The physiological effects of IKK/NF-KappaB mediated repression of cell cycle regulated, E2F target genes will also be evaluated.