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Contact Information:

Dept. of Microbiology and Immunobiology
Harvard Medical School
77 Avenue Louis Pasteur
NRB-939I
Boston, MA 02115

phone: 617-432-1960
fax: 617-432-2689
email:

     

Research Summary

Studies of oncogenic viruses in animal systems have led to important discoveries with relevance to human cancers. Our lab has focused on polyoma virus and the mouse as its natural host. Early work demonstrated the persistence and expression of a portion of the viral genome in transformed cells. Isolation and characterization of non-transforming mutants led to the identification of specific viral T (tumor) antigens and their roles in virus replication and cell transformation. We devised a procedure to identify host proteins and pathways through which the T antigens act (1). The transcription factor p150Sal2 targeted by the large T antigen has growth-arrest and proapoptotic functions (2-4). We are exploring p150Sal2 as a suppressor of ovarian and possibly other forms of cancer.

Sialoglycolipids (gangliosides) function as virus receptors (5). Together with crystallographers, we elucidated how different virus strains bind to sialic acid. Important determinants of virulence and tumorigenicity reside in the major capsid protein VP1 based on their effects on receptor recognition and virus spread (6).

A major challenge has been to understand the host genetics underlying susceptibility and resistance to the virus in different inbred strains of mice. Genes that shape specific aspects of immune responses at the innate (7) and adaptive (8) levels have been partially elucidated. Host factors that govern metastatic behavior of virus-induced osteosarcomas have also been identified (9). We currently focus on polymorphisms in toll-like receptor-4 and their effects on cytokine responses elicited by the virus, and also on the role of a natural antibody (IgM) able to confer resistance to the virus.

Selected Publications

1. Li D, et al. (2001). A tumor host range selection procedure identifies p150(sal2) as a target of polyoma virus large T antigen. Proc Natl Acad Sci U S A 98(25):14619-14624.

2. Li D, et al. (2004). P150Sal2 Is a p53-independent regulator of p21Cip1/Waf1. Mol. Cell Biolo. 24:3885-3893.

3. Gu H, et al. (2011). DNA-binding and regulatory properties of the transcription factor and putative tumor suppressor p150Sal2. Biochim. Biophys Acta 1809:276-83.

4. Sung CK, et al. (2011). Transcriptional and posttranslationmal regulation of the quiescence factor and putative tumor suppressor p150Sal2. FASEB J. 25(4):1275-83.

5. Tsai B, et al. (2003). Gangliosides are receptors for murine polyoma virus and SV40. EMBO J. 22(17):4346-55.

6. Carroll J, et al. (2007). Receptor Binding and Oncogenic Properties of Polyoma Viruses Isolated from Feral Mice. PLoS Pathogens 2007 Dec;3(12):e179.

7. Velupillai P, et al. (2006). Polyoma Virus-Like Particles Elicit Polarized Cytokine Responses in APCs from Tumor-Susceptible and -Resistant Mice. J.Immunol.176:1148-1153.

8. Lukacher AE, et al. (1995). Susceptibility to tumors induced by polyoma virus is conferred by an endogenous mouse mammary tumor virus superantigen. J Exp Med. 1995 181(5):1683-92.

9. Velupillai P, et al. (2010). Polyoma virus-induced tumors in inbred strains of mice: host determinants of metastasis. PLoS Pathogens 2010 Jan 22;6(1):e1000733