|Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2003: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2002: ¥1,900,000 (Direct Cost: ¥1,900,000)
This study has been aimed to elucidate the role(s) of endocytosed midkine (MK), a heparin-binding growth factor. MK is implicated in cancer development, neural survival, and inflammation. One of its receptors is LDL receptor-related protein (LRP), a member of the LDL receptor family. We demonstrated in this study that LRP is responsible for MK endocytosis, endocytosed MK binds to the nucleo-cytoplasmic shuffle protein nucleolin, and the nucleolin-bound MK enters the nucleus. This nuclear targeting by MK is needed for MK-mediated cell survival. We further clarified that the nuclear targeting MK is degraded by the proteasome system. Thus, proteasome inhibitors promote MK stability in the nucleus, and cytoplasmically expressed MK is polyubiquitinated. The N-terminal half domain of MK is important for proteasome-mediated degradation, while the C-terminal half domain is sufficient for nuclear localization. In summary, this study has revealed an important biological function of endocytosed nuclear targeting MK, i.e. anti-apoptosis, and a degradation mechanism of an endocytosed growth factor. We also report some important findings as to MK and cancer, including validity as a tumor marker as well as a molecular target for cancer therapy.