PML oncogenic domains - intranukleäre Strukturen in der Kontrolle von Transkription und Tumorentstehung PML oncogenic domains - intranuclear structures controlling transcription and tumor development

我们一直在研究病毒和细胞癌蛋白对p53肿瘤抑制蛋白的影响，阐明p53不稳定的机制和核输出的作用。此外，我们发现一种腺病毒癌蛋白E4orf3作为一种内部调节剂，抑制腺病毒E1B-55 kDa的p53拮抗功能。我们现在计划将我们未来的工作重点放在E4orf3和相关蛋白的功能上。E4orf3结合并部分破坏称为PML致癌结构域（pod）的亚核结构。pod的完整性似乎可以调节白血病细胞的生长，它代表了细胞PML-RAR癌蛋白以及病毒蛋白E4orf3、巨细胞病毒IE1和拉沙病毒z的靶标。我们已经发现这些pod破坏蛋白可以抑制程序性细胞死亡（凋亡），我们目前正在评估其对腺病毒复制的影响。最近的证据表明，pod可能作为转录调控的中心，表明它们可能通过调节基因表达来影响细胞的存活。为了进一步评估pod在肿瘤发生、细胞凋亡抑制和转录中的作用，我们正在测试pod干扰因子对核激素诱导的转录活性的影响。最后，我们将利用重组腺病毒来表达这些因子，试图找到pod调控表达的新基因。这些研究旨在阐明亚核结构在细胞存活、病毒复制和肿瘤发展中的作用。

We have been studying the effects of viral and cellular oncoproteins on the p53 tumor suppressor protein, elucidating the mechanisms of p53-destabilization and the role of nuclear export. In addition, we have found that an adenoviral oncoprotein, E4orf3, acts as an internal regulator and inhibits the p53-antagonizing function of adenovirus E1B-55 kDa. We are now planning to focus our future work on the functions of E4orf3 and related proteins. E4orf3 associates with and partially disrupts a subnuclear structure termed PML oncogenic domains (PODs). The integrity of PODs appears to regulate the growth of leukemic cells, and it represents a target for the cellular PML-RAR oncoprotein as well as the viral proteins E4orf3, cytomegalovirus IE1 and Lassa virus Z. We have found these POD-disrupting proteins to inhibit programmed cell death (apoptosis), and we are currently evaluating the impact of this on adenovirus replication. Recent evidence suggests that PODs may act as centers of transcriptional regulation, suggesting that they might influence the cell's survival by regulating gene expression. To further evaluate the role of PODs in oncogenesis, apoptosis inhibition and transcription, we are testing the effect of POD-disrupting factors on the activity of nuclear hormone-induced transcription. Finally, these factors will be expressed using recombinant adenoviruses, in an attempt to find novel genes with POD-regulated expression. These studies are aimed at elucidating the role of a subnuclear structure in cell survival, virus replication and tumor development.