Colocalization and heteromerization between the two human oncogene POZ/zinc finger proteins, LAZ3 (BCL6) and PLZF
Colocalization and heteromerization between the two human oncogene POZ/zinc finger proteins, LAZ3 (BCL6) and PLZF
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DOI：
10.1038/sj.onc.1203976
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发表时间：
2000-12-14
期刊：
影响因子：
8
通讯作者：
Koken, MHM
中科院分区：
文献类型：
--
作者：
Dhordain, P;Albagli, O;Koken, MHM
大多数急性早幼粒细胞白血病（APL）病例与维甲酸受体α基因与PML（t（15;17））或PLZF（t（11;17））基因之间的复发性易位有关，PML定位于离散的核内结构域，即PML核体，并显示抗癌和促凋亡特性。PLZF编码属于barZ/结构域和Kruppel锌指（POK）家族下的（PO）的转录因子，其直接与PML相互作用，PLZF与另一种POK蛋白LAZ 3（BCL 6）相关，LAZ 3（BCL 6）在许多非霍奇金淋巴瘤（NHL）病例中结构改变，并且可能是错误表达。PLZF和LAZ 3具有许多共同的功能特性：都抑制细胞生长，集中成点状核亚结构域，是序列特异性转录抑制因子，招募组蛋白脱乙酰酶抑制复合物。鉴于这些相似性，我们测试了两种蛋白质是否可以相互靶向，在这里，LAZ 3和PLZF显示出共定位到核点上。此外，截短衍生物的一种蛋白质，其中显示一个弥漫性的核定位，被招募到核点的全长其他。共定位和相互“拯救”是LAZ 3和PLZF之间直接相互作用的结果，如酵母双杂交测定、体外免疫沉淀和GST下拉实验所示。与LAZ 3同聚化相反，酵母中的LAZ 3/PLZF异聚化不仅依赖于POZ/POZ接触，而且还依赖于两个锌指区之间的相互作用以及每个配偶体的锌指区和POZ结构域之间的“交叉”接触。同样，当两种蛋白质在CHO细胞中稳定过表达时，LAZ 3显示出与PLZF配偶体PML的一些共定位，并与酵母中的PML相互作用。最后，内源性LAZ 3和PLZF在骨髓MDS细胞中共诱导并部分共定位。这些数据表明LAZ 3和PLZF之间的物理相互作用是它们同时募集到多蛋白核复合物上的基础，推测其参与转录沉默，并且其完整性（对于APL）和/或功能（对于APL和NHL）可能在肿瘤发生中改变。
Most acute promyelocytic leukemia (APL) cases are associated with recurrent translocations between the gene of retinoic receptor alpha and that of PML (t(15;17)) or PLZF (t(11;17)), PML localizes onto discrete intranuclear domains, the PML-nuclear bodies, and displays anti-oncogenic and pro-apoptotic properties. PLZF encodes a transcription factor belonging to the (PO) under barZ/domain and Kruppel zinc finger (POK) family which interacts directly with PML, PLZF is related to another POK protein, LAZ3(BCL6), which is structurally altered, and presumably misexpressed, in many non-Hodgkin lymphoma (NHL) cases. PLZF and LAZ3 share many functional properties: both inhibit cell growth, concentrate into punctated nuclear subdomains and are sequence-specific transcriptional repressors recruiting a histone deacetylase-repressing complex. Given these similarities, we tested whether both proteins could be targeted by each other, Here, LAZ3 and PLZF are shown to colocalize onto nuclear dots. Moreover, truncated derivatives of one protein, which display a diffuse nuclear localization, are recruited onto nuclear dots by the full-length other. The colocalization and the reciprocal 'rescue' is the result of a direct interaction between LAZ3 and PLZF, as indicated by yeast two hybrid assays, in vitro immunoprecipitations, and GST pull down experiments. In contrast to LAZ3 homomerization, LAZ3/PLZF heteromerization in yeast does not solely depend on POZ/POZ contacts but rather also relies on interactions between the two zinc finger regions and 'cross' contacts between the zinc finger region and the POZ domain of each partner, Likewise, LAZ3 shows some colocalization with the PLZF partner PML upon stable overexpression of both proteins in CHO cells and interacts with PML in yeast. Finally, endogenous LAZ3 and PLZF are co-induced and partially colocalized in myeloid MDS cells, These data indicate that a physical interaction between LAZ3 and PLZF underlies their simultaneous recruitment onto multiproteic nuclear complexes, presumably involved in transcriptional silencing and whose integrity (for APL) and/or function (for APL and NHL) may be altered in oncogenesis.