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Bret A Hassel
 

Bret A Hassel Ph.D.

Academic Title: Associate Professor
Primary Appointment: Microbiology and Immunology
Secondary Appointments: Institute of Human Virology
Bhassel@UMM.EDU
Location: HH 324
Phone: (410) 328-2344 (office)
Phone: (410) 328-2345 (lab)
Fax: (410) 328-6559

Research Interests:

Interferons are part of the body's natural defense against infection by external microbes (such as viruses and bacteria) and against cancer, the uncontrolled proliferation of our own cells. To effectively use interferons in a therapeutic setting, the challenge is to first determine which pathways of interferon action mediate the clinically relevant activities, and then to selectively modulate these pathways to combat human diseases. My laboratory studies two pathways of interferon action that are involved in the antiviral and tumor suppressive activities of interferon. In one pathway, a ribonuclease known as RNase-L inhibits virus replication by degrading viral RNAs, molecules required for the production of viral proteins and new infectious virus. In the absence of virus, this same RNase-L enzyme functions as a tumor suppressor. Evidence of this antitumor activity comes from the finding that patients in which RNase-L is mutated exhibit an increased risk for hereditary prostate cancer. In most cells, RNase-L is present in an inactive form; our research focuses on how the activity of RNase-L is regulated in normal cells, and how this control is altered in cancer cells. Furthermore, we want to determine the mechanism by which RNase-L keeps cell proliferation in check. This information will help us predict the diseases in which interferon therapy will be beneficial, to evaluate the role of RNase-L in the response to interferon, and ultimately to modulate RNase-L activity to enhance its therapeutic activity. The second pathway we study involves a protein known as ISG15 that has distinct activities inside and outside of cells. Inside the cell, ISG15 modifies the activity of a diverse set of proteins. One ISG15 modified protein functions to enhance the activity of interferon and thus is important in regulating interferon-induced pathways. The identification of other ISG15 modified proteins is an area of intense research in my lab. Since ISG15 induction is one of the strongest and earliest responses to microbial infection, we expect that ISG15 modified proteins will be important mediators of host defense. In addition to its role inside of cells, ISG15 is released from cells where it functions as a cytokine to modulate the immune response. Our research is focused on understanding what cells are responsive to extracellular ISG15 and how this affects the immune response. An understanding of how ISG15 is directed towards its intracellular or extracellular functions should permit the manipulation of ISG15 activity for specific therapeutic outcome.

Publications:

Liu, M., Hummer, B.T., Li, X-L. and Hassel, B.A. 2004 Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. Journal of Interferon and Cytokine Research. In press.

Liu, M., Li, X-L., and Hassel, B.A. Proteasome modulates conjugation to the ubiquitin-like protein, ISG15. J. Biol. Chem. 278:1594-602. 2003.

Liu, M., Reimschuessel, R., and Hassel, B.A., Molecular cloning of the fish ISG15 orthologue: a ubiquitin-like gene induced by nephrotoxic damage. Gene. 298:129-139. 2002.

Hummer, B.T., Li, X-L., and Hassel, B.A. (2001) A role for p53 in gene induction by double-stranded RNA. J. Virol. 75, 7774-7777.

Li, X-L., and Hassel, B.A. (2001) Involvement of proteasomes in gene induction by interferon and double-stranded RNA. Cytokine, 14, 247-252

Li, X-L., Blackford, J.A., Judge, C.S., Liu, M., Xiao, W., Kalvakolanu, D.V. and Hassel, B.A. (2000) RNase-L-dependent destabilization ofinterferon-induced mRNAs: a role for the 2-5A system in attenuation of the interferon response. J. Biol. Chem. 275, 8880-8888.

Li, X-L., Blackford, J.A. and Hassel, B.A. (1998) RNase-L mediates the antiviral effect of interferon through a selective reduction of viral RNA during encephalomyocarditis virus infection. J. Virol. 72, 2752-2759.