In tumor microenvironments, multiple cytokines and growth factors are expressed and coordinately regulate the pathogenic alterations. TNF-α and EGF are typical of these secreted ligands and their pathological functions have been extensively studied. Attention has recently been focused on the role of TNF-α in carcinogenesis, tumor angiogenesis and metastasis. On the other hand, overexpression, amplification and mutations of EGFR are involved in carcinogenesis and the progression of several types of cancer. Anti-TNF-α and anti-EGFR agents have already been developed, and are clinically effective against these diseases. Cross talk between different signaling pathways is likely to be important for diverse cellular functions. Therefore, we have investigated the functional interactions of the TNF-α signal and EGFR signal to elucidate new biological processes.

Our research interest is also on the expression of cytochrome P450, which plays a central role in the metabolism of drugs. It is generally recognized that the metabolic pathway determines pharmacological activities and duration period of many kinds of drugs, and an individually different response to pharmacological action is mainly caused by his/her capacity of metabolism. Furthermore, many adverse effects of drugs are due to the altered metabolism by drug-drug interaction. We have been employing mice for the basic research as a model of expression of human P450s. Our research using mice has been performed in vivo and in vitro. We utilize a primary culture of mouse hepatocytes as in vitro system, since expression of metabolizing enzymes including P450s is at high level in the liver.

Publications

• 1. Zhou Y. et al. : Crucial roles of RSK in cell motility by catalysing serine phosphorylation of EphA2. Nat. Commun., 6 : 7679, 2015.
• 2. Sakurai: Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol. Sci., 30 522-530, 2012.
• 3. Nishimura et al.: TAK1-mediated serine/threonine phosphorylation of epidermal growth factor receptor via p38/extracellular signal-regulated kinase: NF-κB-independent survival pathways in tumor necrosis factor alpha signaling. Mol. Cell. Biol., 29 : 5529-5539, 2009.
• 4. Bhadhprasit et al.: Hepatocyte nuclear factor 4α regulates expression of the mouse female-specific Cyp3a41 gene in the liver. Drug Metab. Dispos., 39 : 279-285, 2011.