Covalent modification of PML by the sentrin family of ubiquitin-like proteins
Covalent modification of PML by the sentrin family of ubiquitin-like proteins
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DOI：
10.1074/jbc.273.6.3117
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发表时间：
1998-02-06
影响因子：
4.8
通讯作者：
Yeh, ETH
中科院分区：
文献类型：
--
作者：
Kamitani, T;Nguyen, HP;Yeh, ETH
PML是一种具有肿瘤抑制活性的RING指蛋白，与急性早幼粒细胞白血病的发病机制有关，急性早幼粒细胞白血病是在PML基因与视黄酸受体α（RAR α）基因融合的相互染色体易位后发生的。免疫细胞化学分析表明，PML与一种新的泛素样蛋白共定位在核小体中，这可能会被PML-RAR α：融合蛋白破坏。这种共定位的物理性质是未知的。使用COS细胞表达系统，我们表明，PML是共价修饰的所有三个成员的sentrin家族的泛素样蛋白。PML的共价修饰需要中心蛋白C末端附近的保守Gly残基。PML的Sentrinization是高度特异性的，因为NEDD 8和泛素都不能修饰PML。对于RanGAP 1通过泛素样蛋白的sentrin成员的共价修饰也观察到类似的特异性。这些观察结果突出了sentrin化途径的精细底物特异性。在急性早幼粒细胞白血病中，有两种形式的PML-RAR α融合蛋白被报道，但这两种融合蛋白均不能被敏化，因此，PML和PML-RAR α的差异敏化可能在调节PML的生物学功能和急性早幼粒细胞白血病的发病机制中起重要作用。
PML, a RING finger protein with tumor suppressor activity, has been implicated in the pathogenesis of acute promyelocytic leukemia that arises following a reciprocal chromosomal translocation that fuses the PML gene with the retinoic acid receptor alpha (RAR alpha) gene. Immunocytochemical analysis has demonstrated that PML is co-localized with a novel ubiquitin-like protein in the nuclear bodies, which could be disrupted by the PML-RAR alpha: fusion protein. The physical nature of this co-localization is unknown. Using a COS cell expression system, we show that PML is covalently modified by all three members of the sentrin family of ubiquitin-like proteins. Covalent modification of PML requires the conserved Gly residue near the C termini of sentrin proteins. Sentrinization of PML is highly specific because neither NEDD8 nor ubiquitin could modify PML. Similar specificity is also observed for the covalent modification of RanGAP1 by the sentrin member of ubiquitin-like proteins, These observations highlight the fine substrate specificity of the sentrinization pathway. In acute promyelocytic leukemia, two forms of PML-RAR alpha fusion proteins have been reported, Remarkably, both forms of PML-RAR alpha fusion proteins could not be sentrinized, Thus differential sentrinization of PML and PML-RAR alpha could play an important role in regulating the biological function of PML and in the pathogenesis of acute promyelocytic leukemia.