Research

INDIVIDUAL RESEARCHER

Jonathan A. Harton , Ph.D.
Assistant Professor
e-mail: hartonj@mail.amc.edu

Education

1995 - Ph.D. from The University of Iowa

Current Research

The Harton lab is focused on molecular regulation of immune responses relevant to innate immunity, inflammation, and cancer. Two main projects are ongoing. The first project examines the transcriptional control of class II MHC genes as it relates to antigen presentation and tumor recognition. At the molecular level we are dissecting the ability of a transcriptional regulator, CIITA, to differentially regulate HLA-DR and its chaperones invariant chain and HLA-DM. CIITA's influence on MHC II transcription is highly regulated and involves CIITA's GTP-binding domain, leucine rich repeats, phosphorylation, ubiquitination, and interactions with a host of transcription factors. We hypothesize that differences in regulation of CIITA-responsive genes influences antigen presentation. This is important for clinical problems ranging from arthritis to multiple sclerosis and from transplant biology to cancer. While assessing the mechanisms of CIITA's transactivator function at the molecular level, at the level of disease, we are employing molecular tools towards understanding how class II MHC contributes to tumor elimination, equilibrium and escape in the mouse models of melanoma and breast cancer. The second project examines the role of intracellular pathogen receptor proteins of the NLR family involved in innate immunity and inflammation. These receptors are structurally related to CIITA and have the interesting property of regulating IL-1beta and IL-18 production as well as occasionally promoting cell death. This area of study has implications for infectious disease and inflammatory syndromes principally, but is likely relevant to cancer as well. We are currently interested in the molecular biology of host responses to the potential bioterrorism agents, Bacillus anthracis and Francisella tularensis, the causative agents of Anthrax and Tularemia. Our current focus is on the NLR proteins that mediate organism specific responses and how these are regulated at the molecular level. One of these proteins, POP2 prevents the interaction of essential players in the NLR-inflammatory pathway and inhibits other intracellular signals (NF-kB). This dual regulatory role is likely important in multiple inflammatory conditions. Since NF-kB is frequently constitutively active in tumors we are also exploring the mechanism and utility of inhibiting NF-kB in tumor cells.

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References

1. Bewry N.N., Bollick S., Wright K.L., Harton J.A. 2007 GTP-dependent recruitment of CIITA to the class II MHC promoter. Journal of Biological Chemistry 282:26178.



2. Bedoya F., Sandler L.L., Harton J.A. 2007 Pyrin-only protein 2 modulates NF-kappaB and disrupts ASC:CLR interactions. Journal of Immunology 178:3837.



3. Harton J.A., Linhoff M.W., Zhang J., Ting J.P. 2002 Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. Journal of Immunology 169:4088.



4. Harton J.A., Zika E., Ting J.P. 2001 The histone acetyltransferase domains of CREB-binding protein (CBP) and p300/CBP-associated factor are not necessary for cooperativity with the class IItransactivator. Journal of Biological Chemistry 276:38715.



5. Harton J.A., Cressman D.E., Chin K.C., Der C.J., Ting J.P. 1999 GTP binding by class II transactivator: role in nuclear import. Science 285:14022