There are eight human tumor viruses, including hepatitis B virus and human papilloma virus, and they are associated with around 10-15 % of human cancers including hepatoma and cervical carcinoma. However, effective therapeutics against these malignancies are not available. We study the mechanism of leukemogenesis of adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1), and object the understanding of the common and specific mechanisms of oncogenesis by the tumor viruses. Based on the study, we object the development of new therapeutics to ATL and other virus-associated malignancies.
Project#1Molecular mechanism of HTLV-1-associated diseases
HTLV-1 is a causative retrovirus of ATL and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). We are interested in how HTLV-1 causes ATL and HAM/TSP. HTLV-1 encodes a viral oncoprotein Tax, playing central roles in HTLV-1 pathogenesis. We isolated several host proteins interacting with Tax, such as USP10, and found that it plays pivotal roles in cellular stress response as well as HTLV-1 pathology as shown below
Project#2USP10 controls cellular stress response
USP10 is a component of stress granules (SG) induced by various stress agents including UV, oxidant (arsenate) and viral infection. We found that USP10 inhibits stress-induced reactive oxygen species (ROS) production and ROS-dependent apoptosis by forming SG. We are studying how USP10 control stress responses
Project#3USP10 is a target molecule of arsenate induced apoptosis of leukemic cells
Arsenate is used for therapeutics against acute promyelocitic leukemia. In addition, arsenate showed a promising therapeutic effect against ATL. Nevertheless, the molecular mechanism of arsenate action has not been elucidated yet. We found that USP10 is a target molecule of arsenate to kill ATL cells and HTLV-1-transformed T-cell lines. Arsenate induced apoptosis of ATL cells more effectively than other human T-cell lines through inefficient function of USP10 in ATL. We are studying the molecular mechanism of USP10-mediated apoptosis inhibition. We are also searching the signaling pathway augmenting arsenate sensitivity to develop more effective ATL therapeutics.