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

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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.