My current research interests are: (a) to identify metabolic oxidative stress-induced signal transduction pathways, (b) to develop a strategy for targeted therapy. I previously observed that tumor microenvironmental stress can induce the synthesis of angiogenic factors such as basic fibroblast growth factor (bFGF). To explain this phenomenon, I hypothesized that environmental stresses activate special transcription factors, referred to as activating protein-1 (AP-1). The activated AP-1 factors (Jun and Fos proteins) bind to the regulatory region of the bFGF gene, triggering new gene expression. This hypothesis was supported by my previous studies, which demonstrated that the synthesis and phosphorylation of c-Jun are required for the induction of bFGF gene expression by glucose deprivation. I also observed that the increased c-Jun phosphorylation induced by glucose deprivation was mediated through the SAPK signaling pathway involving c-Jun N-terminal kinase (JNK1).
Recently, I have investigated how the increased hydroperoxide production induced by oxidative stress is responsible for triggering signal transduction pathways. I postulate that glutaredoxin, a redox-regulatory protein, recognizes the metabolic oxidative stress and triggers the ASK1-SEK1-JNK1 signal transduction pathway. The guiding hypothesis is that glucose deprivation raises the intracellular level of reactive oxygen species and increases the level of oxidized glutathione. Glutaredoxin, which contains two redox-active half-cystine residues (Cys-Pro-Tyr-Cys) in an active center, recognizes metabolic oxidative stress through catalysis of thiol-disulfide interchange reactions with oxidized molecules such as oxidized glutathione. The oxidized glutathione dissociates from ASK1 and subsequently activates the ASK1-SEK1-JNK1 signal transduction pathway. Currently, I am further extending my studies to examine the role of the ASK1-SEK1-JNK1-HIPK1 signal in Daxx relocalization and the role of JNK-interacting scaffolding proteins (JIPs) in the regulation of Akt activity during metabolic oxidative stress.
Currently, I am attempting to develop a new strategy for treating HER-2/neu overexpressing cancer. Cancer cells that resist conventional chemotherapeutic agents can be induced to undergo apoptotic death by engagement of death receptors (DR4 and DR5) expressed on their membrane surface by TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). While TRAIL is a promising anticancer agent, several studies indicate that TRAIL-induced apoptosis is inhibited by survival signals delivered by HER-2/neu. I postulate that HER-2/neu inhibits TRAIL-induced apoptosis via activation of the PI(3)K-Akt-NF-kB survival signaling pathway. Thus, I am investigating whether interrupting the survival signaling pathway controlled by HER-2/neu sensitizes cancer cells to TRAIL-induced cytotoxicity without incurring prohibitive toxicity to normal tissues.
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