Wei Wenyi, Jin Jianping, Schlisio Susanne, Harper J Wade, Kaelin William G
Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cancer Cell. 2005 Jul;8(1):25-33. doi: 10.1016/j.ccr.2005.06.005.
The c-Jun and c-Myc oncogenic transcription factors are highly unstable proteins due to polyubiquitination. Similar to c-Myc, we report here that phosphorylation of c-Jun by GSK3 creates a high-affinity binding site for the E3 ligase Fbw7, which targets c-Jun for polyubiquitination and proteasomal degradation. In keeping with this, we found that c-Jun levels were inversely related to GSK3 activity in mammalian cells that had entered the cell cycle. Importantly, phosphorylation of c-Jun by GSK3 requires a priming phosphorylation event at Ser-243. Ser-243 is mutated to phenylalanine in v-Jun and allows it to escape recognition by Fbw7. These findings explain the enhanced stability and oncogenicity of v-Jun relative to its cellular counterpart and reveal that GSK3 and Fbw7 coordinately regulate c-Jun and c-Myc.
c-Jun和c-Myc致癌转录因子由于多聚泛素化作用而成为高度不稳定的蛋白质。与c-Myc类似，我们在此报告，糖原合酶激酶3（GSK3）介导的c-Jun磷酸化作用为E3连接酶Fbw7创造了一个高亲和力结合位点，该连接酶将c-Jun作为多聚泛素化和蛋白酶体降解的靶点。与此相符的是，我们发现在进入细胞周期的哺乳动物细胞中，c-Jun水平与GSK3活性呈负相关。重要的是，GSK3介导的c-Jun磷酸化作用需要在丝氨酸243位点发生起始磷酸化事件。在v-Jun中，丝氨酸243突变为苯丙氨酸，使其能够逃避Fbw7的识别。这些发现解释了v-Jun相对于其细胞内对应物具有更高的稳定性和致癌性，并揭示了GSK3和Fbw7协同调节c-Jun和c-Myc。
