Signal transducing complexes induced by the herpesvirus ateles oncoprotein Tio in human T cells

• Applicant: Privatdozentin Dr. Brigitte Biesinger-Zwosta
• Subject Area: Virology
• Term: from 2006 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 34159084

Transcription factors of the NF-κB family are involved in multiple physiological processes like development, apoptosis, proliferation, and inflammation. Their dysregulation contributes to pathological processes including various cancers and immunoproliferative disorders. NF-κB proteins are increasingly recognized as key factors of hematopoietic malignancies and are activated by the viral oncoproteins of human T-cell leukemia virus type 1 (HTLV-1), Epstein- Barr virus (EBV), and Kaposi sarcoma-associated herpesvirus (KSHV, HHV-8). Our model system are human T lymphocytes growth-transformed by a recombinant herpesvirus saimiri expressing the herpesvirus ateles oncoprotein Tio. The proliferation of these cells depends on the activity of the canonical NF-κB-regulating kinase, IKKβ. Activation of canonical NF-κB in this context is attributed to an interaction of Tio with the ubiquitin ligase TRAF6, which is known to act upstream of IKKβ. In addition, Tio employs two genetically separable mechanisms to activate non-canonical NF-κB signaling: enhanced expression of the prototypical proteins, RelB and p100, and processing of p100 to p52. The proposed study now wishes to utilize Tio and its mutants to address two major conundrums of non-canonical NF-κB signaling: the details of p100 processing and target gene specificity. The anticipated information shall help to define novel therapeutic strategies for diseases associated with aberrant non-canonical NF-κB activation.

• DFG Programme: Research Grants