Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus
Conjugation with the ubiquitin-related modifier SUMO-1 regulates the partitioning of PML within the nucleus
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DOI：
10.1093/emboj/17.1.61
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发表时间：
1998-01-02
期刊：
影响因子：
11.4
通讯作者：
Dejean, A
中科院分区：
文献类型：
--
作者：
Müller, S;Matunis, MJ;Dejean, A
PML蛋白最初是在急性早幼粒细胞白血病（APL）中作为致癌性PML- rar α嵌合体的一部分被发现的，它集中在离散的亚核结构中，与某些类型的核体相对应，这些结构在APL细胞中被破坏，维甲酸（RA）可以触发它们的重组，与这种类型的白血病的治疗效果相关。最近，三氧化二砷(as （2)O(3)）被发现是一种有效的抗白血病药物，与RA类似，在APL细胞中，As2O3触发PML- rar α的快速降解，并促进完整核体的恢复。在非APL细胞中，泛素样蛋白SUMO-1以可逆和磷酸化依赖的方式共价附着在野生型PML的一个亚群上。未修饰形式的PML存在于可溶性核质部分，而sumo -1多修饰形式的PML仅在PML核体中被划分，As2O3处理显著增加了SUMO-1-PML偶联物的数量，随后在扩大的核体中积累。与PML- rar α相比，PML的总量在As2O3处理后36小时内似乎保持不变。这些发现表明，PML与SUMO-1的结合调节了其细胞内定位，并表明SUMO-1的翻译后修饰可能比之前所怀疑的更广泛地参与了蛋白质靶向不同亚细胞结构的过程。他们提供了额外的证据，证明“泛素样”翻译后修饰的作用并不局限于降解信号。
The PML protein, identified first as part of the oncogenic PML-RAR alpha chimera in acute promyelocytic leukemia (APL), concentrates within discrete subnuclear structures, corresponding to some types of nuclear bodies, These structures are disrupted in APL cells, and retinoic acid (RA) can trigger their reorganization, correlating with its therapeutic effect in this type of leukemia, Recently, arsenic trioxide (AS(2)O(3)) was identified as a potent antileukemic agent which, similarly to RA, induces complete remissions in APL patients: Here we show that, in APL cells, As2O3 triggers rapid degradation of PML-RAR alpha and provokes the restoration of intact nuclear bodies, In non-APL cells, the ubiquitin-like protein SUMO-1 is covalently attached to a subset of wild-type PML in a reversible and phosphorylation-dependent manner. The unmodified form of PML, is found in the soluble nucleoplasmic fraction, whereas the SUMO-1-polymodified forms of PML are compartmentalized exclusively in the PML nuclear bodies, As2O3 administration strikingly increases the pool of SUMO-1-PML conjugates that, subsequently, accumulate in enlarged nuclear bodies, In contrast to PML-RAR alpha, the overall amount of PML seems to remain unaltered up to 36 h following As2O3 treatment, These findings indicate that the conjugation of PML with SUMO-1 modulates its intracellular localization and suggest that post-translational modification by SUMO-1 may be more generally involved than previously suspected in the targeting of proteins to distinct subcellular structures, They provide additional evidence that the role of 'ubiquitin-like' post-translational modification is not limited to a degradation signal.