Qing Guoliang, Qu Zhaoxia, Xiao Gutian
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5324-9. doi: 10.1073/pnas.0609914104. Epub 2007 Mar 15.
The C-terminal, partially truncated forms of the NF-kappaB2/p52 precursor p100, p100DeltaCs, manifest constitutive processing and oncogenic ability, although the responsible mechanisms remain unknown. Here, we report that p100DeltaCs are specifically processed in association with binding to promoter DNA-containing kappaB sites. In the nucleus, p100DeltaCs bind to the kappaB promoter DNA and subsequently recruit the proteasome to form a stable proteasome/p100DeltaC/DNA complex, which mediates the processing of p100DeltaCs. Notably, the processing at the kappaB promoter is initiated by a proteasome-mediated endoproteolytic cleavage at amino acid D(415) of p100DeltaCs, and the processed p52, but not the precursors themselves, is oncogenic by up-regulating a subset of target genes. Our studies demonstrate a different mechanism of p100 processing and also present evidence showing that the proteasome modulates the action of transcription factors at promoter regions through endoproteolysis.
核因子-κB2/p52前体p100的C末端部分截短形式p100DeltaCs表现出组成型加工和致癌能力，尽管其相关机制尚不清楚。在此，我们报道p100DeltaCs与含κB位点的启动子DNA结合时会被特异性加工。在细胞核中，p100DeltaCs与κB启动子DNA结合，随后招募蛋白酶体形成稳定的蛋白酶体/p100DeltaC/DNA复合物，该复合物介导p100DeltaCs的加工。值得注意的是，κB启动子处的加工由蛋白酶体介导的p100DeltaCs氨基酸D(415)处的内蛋白水解切割引发，并且加工后的p52而非前体本身通过上调一部分靶基因而具有致癌性。我们的研究证明了p100加工的不同机制，并且还提供了证据表明蛋白酶体通过内蛋白水解调节启动子区域转录因子的作用。
