||Wednesday,22 April 2015, 17:00～18:30
|| Seminar-shitsu 1, IDAC Research building 7F
||Role of small GTPase Ral in the pathophysiology of inflammatory bowel disease and colitis-associated cancer
||Dr. Hiroshi Nakase
||Department of gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University
||Horiuchi, Hisanori Dept.Molecular and Cellular Biology (ex:8463)
||Recently, the number of patients with inflammatory bowel diseases (IBD) is still increasing in Japan, that develops in youth and is for life long treated as an intractable disease. Furthermore, IBD is known to be associated with inflammation-associated cancer. Research has so far indicated that inflammatory cytokines such as TNF-α and IL-6 are produced by infiltrated macrophages and lymphocytes and their local concentration is increased. Then continuous elevation of these cytokines induces colitis-associated cancer (CAC) via activation of NFκB system in cells. Small GTPases are molecular switches of cellular signaling. Normally, they are activated by GDP/GTP exchange mediated by the guanine nucleotide exchange factors (GEFs) and inactivated by GTP hydrolysis mediated by the GTPase activating proteins (GAPs). It is widely known that a small GTPase Ras is continuously activated by the point mutation in many human cancer cells. Ral is a member of Ras family proteins and known to regulate tumorigenesis and invasion/metastasis of various cancers. So far, 6 types of RalGEFs are identified and 4 of them are direct effectors of Ras. As for RalGAP, its activity has been reported about 20 years ago and finally identified by Dr. Horiuchi’s group in 2009. They are heterodimers consisted of either α1 or α2 subunit and its common β subunit. Here, we investigated a role of Ral in the pathophysiology of IBD and CAC by using RalGAPα2 KO mice and found that Ral-RalGAP pathway are involved in mouse colitis model and colitis-associated cancer. I will discuss about the results in my talk.