Department of Biological Chemistry and Pharmacology

Professor of Biological Chemistry and Pharmacology

College of Medicine
Department of Biological Chemistry and Pharmacology, Comprehensive Cancer Center

174 Rightmire Hall
1060 Carmack Road
Columbus, Ohio 43210
Phone: 614-292-2910
Fax: 614-292-5379
Email: hai.2@osu.edu

Current Research: Maladaptation of cells to various signals plays important roles in the pathogenesis of many human diseases. The current focus of my laboratory is to study the maladaptive processes in the development of breast cancer and diabetes. In both diseases, inflammatory signals exacerbate the diseases. We are investigating how inflammatory signals in conjunction with other stress signals affect various cellular machineries that regulate signal transduction, transcription, apoptosis, cell migration, angiogenesis and metastasis.

The approach we take is to focus on a stress-inducible gene ATF3, which encodes a member of the ATF/CREB transcription factors. Our strategy is to use ATF3 — as a handle — to probe the stress responses and gain insights to the roles of cellular adaptations to stress signals in disease development.

ATF3 as an adaptive-response gene and a “hub” in the biological networks ATF3 is a member of the ATF/CREB transcription factors, which all share a common DNA binding motif — the basic region-leucine zipper (bZip) motif — and bind to the consensus sequence TGACGTCA in vitro, albeit with different affinity. Overwhelming evidence indicates that ATF3 is induced by a variety of stress signals. However, some of the signals that induce ATF3 expression do not fit the conventional definition of stress signals. Thus, it is overly simplistic to characterize ATF3 as a stress-inducible gene; rather, we suggest characterizing it as an adaptive-response gene that participates in cellular processes to adapt to extra- and/or intra-cellular changes. The list of the signals that can induce ATF3 expression is considerably long, including some seemingly unrelated or sometimes conflicting signals such as cytokines, calcium influx, hypoxia, nutrient deprivation, and serum stimulation. Thus, it appears that ATF3 is a key gene for the cells to respond to perturbation of cellular homeostasis. Borrowing the hub concept from the network theory, we suggest that ATF3 is a “hub” in the biological networks.

Breast cancer research
We found that ATF3 has a dichotomous role in cancer development. It functions as a tumor suppressor in non-transformed mammary epithelial cells but an oncogene in malignant breast cancer cells. Thus, how the cells “interpret” the expression of ATF3, an adaptive-response gene, depends on the “context” of the cells — the milieu of various events ongoing in the cells. In the malignant breast cancer cells, ATF3 promotes cell motility and up-regulates many genes involved in epithelia-mesenchymal transition (EMT), further supporting an oncogenic role of ATF3 in this context. Interestingly, the ATF3 gene is amplified and its expression up-regulated in most of the breast tumor samples we have examined thus far (>200 samples for expression studies), suggesting that ATF3 is likely to play a relevant role in human breast cancer development. We are now examining the roles of ATF3 in stroma-cancer interactions and tumor metastasis. In light of the recent findings that ATF3 regulates innate immune response — a process known to play an important role in cancer development — we are also examining the roles of ATF3 in the interplays between innate immunity and cancer development.

Diabetes research
We found that ATF3 is induced in the pancreatic beta cells by many stress signals relevant to diabetes, including inflammatory cytokines, high fatty acids, and high glucose. Functionally, induction of ATF3 promotes apoptosis in the beta cells and our data indicate that it does so, at least in part, by repressing IRS2, a potent pro-survival factor in beta cells. Deletion of ATF3 protects beta cells from stress-induced apoptosis under various paradigms. Based on these findings, we are testing the idea that deletion of ATF3 “dampens” islet stress responses and may protect beta cells in islets transplantation. In addition to the roles of ATF3 in the islets — the graft — we are also testing the roles of ATF3 in the host immune system to determine how it may affect the host-graft interactions. Since islet transplantation is a clinically viable treatment for diabetes, these studies may lead to future applications to improve therapy for diabetes.

Techniques and Models:
The methods we use include those in the areas of biochemistry, molecular biology, genetics, cell biology, pathology and physiology. The experimental systems we use include mammalian cells (primary and cell lines), transgenic/knockout mice and clinical samples.
• Molecular biology: cloning, BAC recombineering, RNA preparation and analyses (real-time PCR, northern), RNAi, immuno-blotting, EMSA, chromatin immunoprecipitation (ChIP), kinase assays and transcription assays.
• Cell biology: in situ hybridization, immnuocytochemistry, apoptosis assays, cell cycle analyses, immunofluorescent assay, confocal microscopy, cell motility assay, angiogenesis assay and analyses of macrophages.
• Biochemistry: protein production by various expression systems, protein fractionation and chromatography.
• Genetics and physiology: xenograft tumor models, syngeneic and allogeneic islet transplantation in mice, production and analyses of genetically modified mice, including transgenic, knock-out and knock-in mice.
• Microarray, proteomics and bioinformatics

PubMed articles

Education:
PhD: Massachusetts Institute of Technology
Postdoctoral: Harvard University

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