Department of Cell Biology, Key Laboratory of the Education Ministry for Cell Differentiation and Apoptosis, Institutes of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
J Biol Chem. 2010 Apr 23;285(17):12906-15. doi: 10.1074/jbc.M109.071431. Epub 2010 Feb 24.
Small ubiquitin-like modifier (SUMO) 2/3 is known to conjugate to substrates in response to a variety of cellular stresses. However, whether and how SUMO2/3-specific proteases are involved in de-conjugation under cell stress is unclear. Here, we show that low doses of hydrogen peroxide (H(2)O(2)) induce an increase of the SENP3 protein, which removes SUMO2/3 from promyelocytic leukemia (PML). Low dose H(2)O(2) causes SENP3 to co-localize with PML bodies and reduces the number of PML bodies in a SENP3-dependent manner. Furthermore, de-conjugation of SUMO2/3 from PML is responsible for the accelerated cell proliferation caused by low dose H(2)O(2). Knocking down PML promotes basal cell proliferation as expected. This can be reversed by reconstitution with wild-type PML but not its mutant lacking SUMOylation, indicating that only the SUMOylated PML can play an inhibitory role for cell proliferation. Thus, SENP3 appears to be a key mediator in mild oxidative stress-induced cell proliferation via regulation of the SUMOylation status of PML. Furthermore, SENP3 is over-accumulated in a variety of primary human cancers including colon adenocarcinoma in which PML is hypo-SUMOylated. These results reveal an important role of SENP3 and the SUMOylation status of PML in the regulation of cell proliferation under oxidative stress.
小泛素样修饰物（SUMO）2/3 已知可在响应各种细胞应激时与底物结合。然而，SUMO2/3 特异性蛋白酶是否以及如何参与应激下的去结合尚不清楚。在这里，我们显示低剂量的过氧化氢（H₂O₂）诱导 SENP3 蛋白增加，该蛋白从早幼粒细胞白血病（PML）中去除 SUMO2/3。低剂量的 H₂O₂导致 SENP3 与 PML 体共定位，并以 SENP3 依赖性方式减少 PML 体的数量。此外，SUMO2/3 从 PML 的去结合负责由低剂量 H₂O₂引起的细胞增殖加速。敲低 PML 如预期的那样促进基础细胞增殖。这可以通过野生型 PML 的重建来逆转，但不能通过缺乏 SUMO 化的突变体来逆转，表明只有 SUMO 化的 PML 才能对细胞增殖发挥抑制作用。因此，SENP3 似乎是通过调节 PML 的 SUMO 化状态在轻度氧化应激诱导的细胞增殖中起关键介导作用。此外，SENP3 在多种原发性人类癌症中过度积累，包括 PML 低 SUMO 化的结肠腺癌。这些结果揭示了 SENP3 和 PML 的 SUMO 化状态在氧化应激下细胞增殖调节中的重要作用。
