Mechanisms of molecular chaperones in viral and cellular oncogenesis

Molecular chaperones are required for maintenance of cell homeostasis. It has been well known that dysregulation of these proteins has significant impact on the process of oncogenesis. Our research interest is to understand the mechanisms that alteration of the expression and activity of molecular chaperones involves in oncogenic process by modulating cellular signaling pathways. Tid1 is a member of molecular chaperone family, which is structurally related to Drosophila tumor suppressor Tid56. Tid1 suppresses proliferation of certain types of cancer by interfering with oncogenic signaling pathways including NF-kappaB. This putative tumor suppressor is targeted by viral oncoproteins such as Tax of human T cell leukemia virus type 1 (HTLV-1) and E7 of human pappilloma virus type 16 (HPV16). Notably, Tid1 is downregulated in about 50% of the patients with large granular lymphocyte (LGL) leukemia, a T-cell type of leukemia associated with an infection of HTLV-like virus. We have established T-LGL leukemia model to investigate the mechanism of Tid1 down-regulation in correlation with leukemogenesis.
Tid1 is expressed abundantly in heart, liver, skeletal muscle and blood cells but at a low level in normal lung tissue. However, Tid1 is over-expressed in lung adenocarcinoma and mesothelioma. Like SV40 large T antigen (LT), Tid1 constitutes a signature J domain in complex with Hsc70. The J-domain containing viral oncoprotein, SV40 LT, induces cell transformation by inactivating the tumor suppressors pRB and p53, and this process requires a functional J domain. This structural property suggests that induction of Tid1 or a potential "œgain of function" mutation may play a critical role in transformation of lung epithelial cells. In other cases, complete loss of expression of Tid1 is associated with certain types of solid tumor. We are investigating the role of Tid1 in transformation of primary human cells induced by viral and cellular oncogenes and the mechanism of Tid1 in regulating IkappaB kinase complex in inflammation and cancer.