| Budget Amount *help |
¥46,700,000 (Direct Cost: ¥46,700,000)
Fiscal Year 2005: ¥8,900,000 (Direct Cost: ¥8,900,000)
Fiscal Year 2004: ¥8,700,000 (Direct Cost: ¥8,700,000)
Fiscal Year 2003: ¥9,600,000 (Direct Cost: ¥9,600,000)
Fiscal Year 2002: ¥10,000,000 (Direct Cost: ¥10,000,000)
Fiscal Year 2001: ¥9,500,000 (Direct Cost: ¥9,500,000)
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| Research Abstract |
Sekiguchi has studied mechanisms of nuclear-cytoplasmic transport of macromolecuar complex, mainly on GTP binding protein Ran related proteins, RCC1, RRAG A/GTR1, DDX3. RCC1 is a chromatin binding protein and a Ran Guanine exchange factor. In this study, we found that Gtrlp interacts to Ran-binding protein, Yrb2p, ribosome biogenesis proteins, Rpcl9p and Nop8p. We also found that RRAG A interacts to GTP binding proteins, RRAG C and RRAG D, and a novel nucleolar protein, NOP132. We isolated hamster temperature-sensitive mutant of DDX3, an RNA DEAD-box helicase playing roles in ribosome biogenesis and translation. DDX3 turned out to play a role in cyclin A expression in hamster cells. Nakayama investigates mammalian Skp2 and Fbw7, which are F-box protein components of an SCF-type ubiquitin ligase. Fbw7 targets c-Myc, Notch, c-Jun, and cyclin E, all of which function to promote cell cycle, for ubiquitin-dependent proteolysis. Clinical evidence suggests that loss of Fbw7 function results i
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n cancer development. We generated mice deficient in Fbw7 and found that the embryos died in utero, manifesting marked abnormalities in vascular development. To investigate the role of Fbw7 in cell-cycle control during cellular differentiation, we have generated mice in which Fbw7 is ablated only in T-cell lineage (Fbw7 conditional knockout mice: CKO). We used two promoters for Cre-expressing transgenic lines, Lck-promoter and CD4-promoter. In both cases, thymic hyperplasia was observed in Fbw7 CKO with specific expansion of CD4+CD8+ population. In normal mice, T cells are mainly proliferated at CD4-CD8-stage, and cell cycle ceases at CD4+CD8+ stage, whereas cell cycle remained activated at CD4+CD8+ stage in Fbw7 CKO. In CD4+CD8+ stage of Fbw7 CKO, c-Myc and Notch highly accumulated, whereas cyclin E levels were unaffected. Fbw7 CKO mice are predisposed to lymphomas. These data suggest that Fbw7 is indispensable for the cell cycle arrest at CD4+CD8+ stage, and loss of Fbw7 results in lymphomatogenesis. Less
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