Cell death induction by the acute promyelocytic leukemia-specific PML/RAR alpha fusion protein
Cell death induction by the acute promyelocytic leukemia-specific PML/RAR alpha fusion protein
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DOI：
10.1073/pnas.94.20.10901
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发表时间：
1997-09-30
影响因子：
11.1
通讯作者：
Pelicci, PG
中科院分区：
文献类型：
--
作者：
Ferrucci, PF;Grignani, F;Pelicci, PG
PML/RAR α是由急性早幼粒细胞白血病特异性t（15; 17），PML/RAR α在造血前体细胞系中的表达诱导分化阻滞并促进存活，我们在此报告PML/RAR α对所有非造血细胞系和大多数测试的造血细胞系具有强效生长抑制作用，PML/RAR α在成纤维细胞中的诱导表达表明，生长抑制的基础是诱导细胞死亡，相关的早幼粒细胞白血病（PML）和维甲酸受体的缺失融合蛋白中RAR α结构域的分析表明，其生长抑制作用依赖于PML氨基末端区域的完整性（RING、B1、B2和卷曲螺旋区）和RAR α DNA结合区，通过免疫荧光和细胞分级分离对相同PML/RAR α缺失突变体的核定位的分析揭示融合蛋白的生物活性与其微斑点定位及其与核基质的关联相关。PML/RAR α的正确核定位需要PML氨基末端区域，而不是RAR α锌指。我们提出，基质相关的微斑点是PML/RAR α的活性位点，并且RAR α序列通过PML序列靶向该特定的核亚结构域对融合蛋白的存活调节活性至关重要。
PML/RAR alpha is the abnormal protein product generated by the acute promyelocytic leukemia-specific t(15;17), Expression of PML/RAR alpha in hematopoietic precursor cell lines induces block of differentiation and promotes survival, We report here that PML/RAR alpha has a potent growth inhibitory effect on all nonhematopoietic cell lines and on the majority of the hematopoietic cell lines tested, Inducible expression of PML/RAR alpha in fibroblasts demonstrated that the basis for the growth suppression is induction of cell death, Deletion of relevant promyelocytic leukemia (PML) and retinoic acid receptor (RAR alpha) domains within the fusion protein revealed that its growth inhibitory effect depends on the integrity of the PML aminoterminal region (RING, B1, B2, and coiled coil regions) and the RAR alpha DNA binding region, Analysis of the nuclear localization of the same PML/RAR alpha deletion mutants by immunofluorescence and cell fractionation revealed that the biological activity of the fusion protein correlates with its microspeckled localization and its association to the nuclear matrix. The PML aminoterminal region, but not the RAR alpha zinc fingers, is required for the proper nuclear localization of PML/RAR alpha, We propose that the matrix-associated microspeckles are the active sites of PML/RAR alpha and that targeting of RAR alpha sequences to this specific nuclear subdomain through PML sequences is crucial to the activity of the fusion protein on survival regulation.