 |
 |
 |
 |
 |
 |
 |
Member Information
Robert Ricciardi, PhD
Professor, Department of Microbiology
University of Pennsylvania Dental School
Office Phone: 215-898-3905
Office Fax: 215-898-8365
Email: ricciardi@biochem.dental.upenn.edu
Website(s):
Education: PhD 1977, University of Illinois
Keywords: None available.
Research and/or Clinical Interests:
The mechanisms by which viral proteins of human DNA viruses regulate gene expression and produce disease and cancer.
Summary:
I. The mechanism of E1A mediated tumorigenesis.
DNA tumor viruses have greatly contributed to our knowledge of transformation and tumorigenesis. In cells transformed by adenovirus 12, the surface levels of the major histocompatibility class I antigens are greatly diminished This reduction of class I antigens on the cell surface enables these transformed cells to escape immunosurveillance by cytotoxic T lymphocytes which contributes to their tumorigenic potential. The viral E1A gene mediates this effect by blocking transcription of the class I promoter. Specifically, the enhancer of the class I promoter is inactivated by two distinct mechanisms. The first involves disabling the activator NF-kB from binding to its cognate recognition site on the enhancer and the second involves strong binding of the repressor COUP-TF to a different recognition site on the enhancer. The mechanisms which regulate the differential binding of NF-kB and COUP-TF to the class I enhancer are being studied. The E1A-12 protein contains a 20 amino acid domain which is required for tumorigenesis, but which functions through an unknown pathway which does not involve down-regulation of class I transcription. This new E1A mediated tumorigenic pathway needs to be explored.
II. Structure and function of the E1A-5 transactivating protein:
Critical to understanding gene expression is the manner by which transcriptional promoters are stimulated by transactivating proteins. The E1A-5 protein of adenovirus contains a 46 amino acid transactivating domain that stimulates promoters by functioning as a bridge between the basal transcription complex and upstream factor binding sites. A zinc finger within the transactivating domain binds to the TATA box binding protein (TBP) and a newly discovered cellular factor, CR3BP, while residues flanking the zinc finger associate with other basal transcription factors, referred to as TAFs. The way in which E1A and the cellular proteins interact needs to be described using genetic, biochemical and structural approaches.
III. The Processivity Factor of HHV-8: mechanism and antiviral targeting
HHV-8 (KSHV) is a newly discovered human herpesviruses which is the etiological agent of Kaposi's sarcoma (KS) and certain B-cell lymphomas. The processivity factor of HHV-8 (PF-8) enables the viral DNA polymerase (Pol-8) to remain on the template and is critical for DNA synthesis. The manner by which PF-8 tethers Pol-8 to the template and functions as a sliding-clamp on the DNA needs to be understood. The usefulness of a novel high throughput assay to identify functional inhibitors of PF-8 that may also serve as antivirals needs to be explored.
Representative Publications:
Liu, X., Ge, R. and Ricciardi, R. P. 1996. Evidence for the involvement of a nuclear NF-kB inhibitor in global down-regulation of the major histocompatibility complex class I enhancer in adenovirus type12-transformed cells. Mol. Cell. Biol. 16: 398-404.
Whalen, S.G., Marcellus, R.C., Whalen, A., Ahn, N. G., Ricciardi, R.P., and Branton, P.E. 1997. Phosphorylation within the transactivating domain of adenovirus E1A protein by MAP kinase regulates expression of early region 4. J. Virol. 71: 3545-3553.
Mazzarelli, J. M., Mengus, G., Davidson, I. , and Ricciardi, R.P. 1997. The transactivating domain of E1A interacts with the C-terminus of human TAFII135. J. Virol. 71: 7978-7983.
Lin, K., Dai, C., and Ricciardi, R. P.1998. Cloning and Functional Analysis of Kaposi's Sarcoma-Associated Herpesvirus DNA Polymerase and Its Processivity Factor. J. Virol. 72: 6228-6232.
