VIRAL ONCOPROTEIN ACTIVATION IN AIDS-RELATED TUMORS

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DESCRIPTION: (Adapted from Applicant's Abstract) Tumor viruses, such as KSHV and EBV, are responsible for the majority of AIDS-related malignancies, including Kaposi's sarcoma and CNS lymphoma. Many tumor viruses share the ability to directly or indirectly inhibit p 53 and pRB tumor suppressor pathways. KSHV vIRF and EBV EBNA2 oncoproteins share a third common feature of inhibiting interferon signaling which may contribute to cell transformation. These investigators have found that vIRF and EBNA2, like adenovirus E1A, bind the transscriptional coadaptor p300 involved in interferon and apoptosis-related transcription. VIRF, EBNA2, and EIA induce the cMYC oncogene promotor in a p300 regulated manner through an interferon-responsive element and cMYC induction is required for vIRF-induced cell transformation. This effect is mediated by an undiscovered transcriptional factor, provisionally called PBF-X, may have general importance for the dysregulation of cMYC in both infectious and non-infectious cancers. This is a collaborative research effort designed to bring together two research groups to systematically examine the effects of p300 binding by vIRF and EBNA2 on MYC induction and apoptotic pathway inhibition. This will be achieved by mapping functional domains of vIRF and EBNA2, and by fine mapping the response element sequences in the cMYC promoter. The effects of p300 binding by EBNA3 and vIRF on p53-dependent and independent apoptotic transcriptional responses will be examined using p53-temperature sensitive mutant cells. Mechanistic studies (e.g. using protein synthesis inhibition and dominant negative inhibitors) will broadly define the pathway for cMYC induction and the contributing role of p300. The identity of PBF-X will be sought from among eight known transcription factors (IRFs1-7 , and Blimp-1) and new candidates will be identified from yeast one- and two-hybrid studies. After PBF-X is identified, knockout mice will be generated for physiologic studies of the this transcriptonal factor. PBF-X is p potential tumor suppressor candidate and LOH and chromosomal breakpoint data will be examinded for mutations involving this locus. A pilot study of tumors, particularly non-Burkitt's NHL with germline cMYC will be examined for PBF-X mutations or LOH to test whether this transcription factor plays a role in human tumorigenesis. These studies will lead to novel approaches in the control of EBV and KSHV-related malignancies in AIDS patients.