Gene Regulation Section, Laboratory of Pathology, National Cancer Institute, Bethesda, MD, USA.
EMBO J. 2011 Mar 2;30(5):846-58. doi: 10.1038/emboj.2011.11. Epub 2011 Feb 1.
c-myc and p53 networks control proliferation, differentiation, and apoptosis and are responsive to, and cross-regulate a variety of stresses and metabolic and biosynthetic processes. At c-myc, the far upstream element binding protein (FBP) and FBP-interacting repressor (FIR) program transcription by looping to RNA polymerase II complexes engaged at the promoter. Another FBP partner, JTV1/AIMP2, a structural subunit of a multi-aminoacyl-tRNA synthetase (ARS) complex, has also been reported to stabilize p53 via an apparently independent mechanism. Here, we show that in response to oxidative stress, JTV1 dissociates from the ARS complex, translocates to the nucleus, associates with FBP and co-activates the transcription of a new FBP target, ubiquitin-specific peptidase 29 (USP29). A previously uncharacterized deubiquitinating enzyme, USP29 binds to, cleaves poly-ubiquitin chains from, and stabilizes p53. The accumulated p53 quickly induces apoptosis. Thus, FBP and JTV1 help to coordinate the molecular and cellular response to oxidative stress.
c-myc 和 p53 网络控制细胞增殖、分化和凋亡，并对各种应激、代谢和生物合成过程做出反应和交叉调节。在 c-myc 上，远上游元件结合蛋白（FBP）和 FBP 相互作用的阻遏物（FIR）通过环化到启动子处结合的 RNA 聚合酶 II 复合物来编程转录。另一个 FBP 伴侣 JTV1/AIMP2 是多氨酰-tRNA 合成酶（ARS）复合物的结构亚基，也被报道通过一种明显独立的机制稳定 p53。在这里，我们表明，在氧化应激的反应中，JTV1 从 ARS 复合物解离，易位到核内，与 FBP 结合并共同激活一个新的 FBP 靶基因，泛素特异性肽酶 29（USP29）的转录。一个以前未被表征的去泛素化酶，USP29 结合、从多聚泛素链上切割并稳定 p53。积累的 p53 迅速诱导细胞凋亡。因此，FBP 和 JTV1 有助于协调对氧化应激的分子和细胞反应。
