Department of Molecular Biology, The Jikei University School of Medicine, 3-25-8 Nishi-shinbashi, Minato-ku, Tokyo, 105-8461, Japan.
Sci Rep. 2018 Feb 14;8(1):3005. doi: 10.1038/s41598-018-21189-0.
The proto-oncogene c-Myc encodes a short-lived protein c-Myc that regulates various cellular processes including cell growth, differentiation and apoptosis. Degradation of c-Myc is catalyzed by the proteasome and requires phosphorylation of Thr-58 for ubiquitination by E3 ubiquitin ligase, Fbxw7/ FBW7. Here we show that a polyamine regulatory protein, antizyme 2 (AZ2), interacts with c-Myc in the nucleus and nucleolus, to accelerate proteasome-mediated c-Myc degradation without ubiquitination or Thr-58 phosphorylation. Polyamines, the inducer of AZ2, also destabilize c-Myc in an AZ2-dependent manner. Knockdown of AZ2 by small interfering RNA (siRNA) increases nucleolar c-Myc and also cellular pre-rRNA whose synthesis is promoted by c-Myc. AZ2-dependent c-Myc degradation likely operates under specific conditions such as glucose deprivation or hypoxia. These findings reveal the targeting mechanism for nucleolar ubiquitin-independent c-Myc degradation.
原癌基因 c-Myc 编码一种短寿命的蛋白质 c-Myc，它调节包括细胞生长、分化和凋亡在内的各种细胞过程。c-Myc 的降解由蛋白酶体催化，需要 Thr-58 的磷酸化，以便被 E3 泛素连接酶 Fbxw7/FBW7 泛素化。在这里，我们表明多胺调节蛋白，抗酶 2（AZ2），在核和核仁中与 c-Myc 相互作用，以加速蛋白酶体介导的 c-Myc 降解，而无需泛素化或 Thr-58 磷酸化。多胺是 AZ2 的诱导剂，也以 AZ2 依赖的方式使 c-Myc 不稳定。通过小干扰 RNA（siRNA）敲低 AZ2 会增加核仁 c-Myc 以及由 c-Myc 促进合成的细胞前 rRNA。AZ2 依赖性 c-Myc 降解可能在特定条件下发生，例如葡萄糖剥夺或缺氧。这些发现揭示了核仁中非泛素依赖的 c-Myc 降解的靶向机制。
