Thomas M. Kristie, Ph.D.

Chief, Molecular Genetics Section

Description of Research Program

Following a primary infection with herpes simplex virus, the individual harbors the virus in a dormant or latent state in neuronal sensory ganglia. The latent virus can subsequently reactivate, resulting in disease ranging from mild recurrent lesions to more significant illnesses, such as viral encephalitis.

Research in the section focuses on the biochemical mechanisms of viral gene expression with particular emphasis on cellular factors that control the viral immediate early (IE) gene expression. The section has identified and isolated specific proteins that are critical for the expression of the viral IE genes during the lytic infection and that may also play significant roles in the reactivation of the virus from the latent state.

The most significant of these, the mammalian C1 factor (HCF-1), is involved in coordinating the viral IE genes transcriptional enhancer complex and co-activating transcription during the lytic cycle. In addition, the subcellular localization of the protein in cells harboring latent virus and its relocalization during the reactivation process has led to a model whereby the C1 factor is a controlling element in the viral lytic-latent cycle. Continuing studies focus upon the identification of additional factors that are similarly involved in this process and the relevance of these factors to normal cellular gene expression, differentiation, and development.

A second focus of the section is the isolation and characterization of site-specific proteases, which play significant roles in the regulation of cellular processes such as signal transduction, apoptosis, and development. My laboratory has developed a genetic screen for site-specific proteases and is presently utilizing this system to characterize cellular and viral proteases and to isolate novel enzymes.

Model of C1 control of reactivation of HSV from latency: C1 is sequestered in the cytoplasm of sensory neurons until reactivation signals (stress, irradiation, etc.) signal its release and transport to the nucleus. In concert with activated transcription factors, C1 activates transcription of the viral IE genes to begin a limited replication-viral reactivation cycle.

Memberships

• American Association for the Advancement of Science
• American Society for Biochemistry and Molecular Biology

Advisory Boards

• Journal of Biomedical Science

Research Group Members

Jodi Vogel, Staff Scientist; Mauricio Nogueira, Postdoctoral Fellow; Bharat Khurana, Postdoctoral Fellow; Aarthi Narayanan, Postdoctoral Fellow; Alison Smoot-Pierce, Staff 

Selected Publications

(View list in PubMed.)

Vogel JL, Kristie TM. The C1 factor (HCF) in The Encyclopedia of Molecular Medicine, T. E. Creighton, Ed., 2001. (John Wiley and Sons, Inc., New York).

Sices HJ, Leusink M, Pacheco A, Kristie TM. Rapid genetic selection of inhibitor-resistant protease mutants: clinically relevant and novel mutants of the HIV protease. AIDS Res. Hum. Retrov. 2001:17, 1255-1261.

Vogel J, Kristie TM. The novel coactivator C1 (HCF) coordinates multiprotein enhancer formation and mediates transcription activation by GABP. EMBO J. 2000:19, 683-690.

Vogel JL, Kristie TM. Autocatalytic proteolysis of the transcription factor-coactivator C1 (HCF): a potential role for proteolytic regulation of coactivator function. Proc. Natl. Acad. Sci. 2000: 97, 9425-9430.

Kristie TM, Vogel JL, Sears AE. Nuclear localization of the C1 factor (HCF) in sensory neurons correlates with initiation of reactivation of HSV from latency. Proc. Natl. Acad. Sci. 1998: 96, 1229-1233.

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