Role of the ETS1 proto-oncogene protein in polyomavirus transcription

Project Summary/Abstract: Polyomaviruses (PyVs) are common in the human virome, but in immunosuppressed individuals can cause a variety of human diseases, including loss of transplanted kidneys, progressive multifocal leukoencephalopathy (a brain demyelinating disease), and human cancers (such as from MCV, and recent studies indicating that the common PyVs, BKV and JCV may also be causing cancers in immunosuppressed patients). The major PyV oncoprotein is Large Tumor-antigen (LT). LT plays many roles in viral infection: genome replication, viral transcriptional regulation, and directly targeting cellular growth suppressors. In addition, LT upregulates many cellular genes required for the proliferative phenotype important for successful viral infection. LT-dependent transcriptional upregulation does not require LT binding to DNA, but rather LT acts as a bridging factor between cellular DNA-binding transcription factors and the cellular TBP/TFIID complex, which then recruits TFIIB and RNA polymerase II. This explains why LT is capable of upregulating so many genes in a manner that is independent of viral LT DNA binding sites. Here we show for the first time preliminary data that the important cellular proto-oncogenic transcription factor, Ets1, is associated with LT, and furthermore, that downregulation of Ets1 abrogates viral transcriptional activation by LT. In this proposal we will investigate the mechanisms by which LT and Ets1 cooperate to regulate viral transcription, and the role Ets1 plays in the PyV viral life cycle. These studies will provide insight into understanding how a major cellular proto-oncogenic transcription factor, Ets1, is recruited and utilized by PyVs for transcription during their viral life cycle. These studies will provide information that will lead to future studies on how the viral LT protein works with Ets1 to produce changes in the cellular transcriptome required to create a hospitable intracellular environment for PyV infection. As Ets1 exerts major global transcriptional effects important for the proliferative phenotype for the majority of human cancers, these studies may also lead to future important insights into the transcriptional roles of LT for cellular transformation and the induction of PyV-induced cancers.