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Research Project:Investigation into the molecular mechanism of cell-growth and cell-death control.
1. Elucidation of physiological function of p27Kip1 that controls cell growth and differentiation
Growth and death are the basic properties of the cell. Disturbance of the control for cell growth and death has been believed as a major cause of carcinogenesis. Cell growth and death do not always take place, rather they are tightly regulated in tissue- and development-specific manners. For example, neurons proliferate only in fetus, but never in adult. The mechanism of this development-specific regulation of cell growth has been largely unclear.
We investigate the physiological roles of factors which control cell cycle and cell death. Recently we focus our interest on the roles of cyclin-dependent-kinase inhibitors (CKI), which negatively regulate cell proliferation, in development and carcinogenesis. Mice lacking p27Kip1, which is the most related CKI to development and growth regulation, were created in our laboratory. The p27Kip1 knockout mice displayed increased body size, and multiple organ hyperplasia in immune, nervous, and reproductive systems. In addition, pituitary tumor frequently arose in these knockout mice, indicating that p27Kip1 is an oncosuppressor molecule. A series of clinical studies suggested that tumors with lower expression of p27Kip1 have poorer prognosis. Thus, we explore the molecular mechanism by which expression level of p27Kip1 is controlled.
2. Elucidation of the molecular mechanism for ubiquitination of p27Kip1
The ubiquitin-proteasome pathway of protein degradation plays an important role in control of the abundance of short-lived regulatory proteins. The ubiquitin-attachment system consists of several components that act in concert. A ubiquitin-activating enzyme (E1) uses ATP to form a thioester bond between itself and ubiquitin, and it then transfers the activated ubiquitin to a ubiquitin-conjugating enzyme (E2). Protein-ubiquitin ligation often requires the participation of a third component, termed ubiquitin ligase (E3). Although the E3 components are thought to be primarily responsible for substrate recognition, they are the least well understood of the enzymes of the ubiquitin-conjugation system.
The SCF complexes, a major class of E3 ligases, consist of the invariable components Skp1, Cul1, and Rbx1/ROC1 as well as a variable component, known as an F-box protein, that binds to Skp1 through its F-box motif and serves as the substrate-recognition subunit. Skp2, an F-box protein with leucine-rich repeats, mediates degradation of p27Kip1.
With the use of gene targeting in embryonic stem (ES) cells, we have now generated mice lacking Skp2. Cells derived from these animals exhibit hyperaccumulation of both cyclin E and p27Kip1, polyploidy, and multiple centrosomes. Consistent with these observations, our biochemical analysis indicates that Skp2 mediates ubiquitin-dependent degradation of cyclin E. Taken together, these data suggest that SCFSkp2 functions as the principal ubiquitin ligase in determining the abundance of cell cycle regulatory proteins at the G1-S transition, thereby ensuring strict control of chromosomal replication and centrosome duplication.
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Taichi Shiraishi,Yuta Katayama,Masaaki Nishiyama,Hirotaka Shoji,Tsuyoshi Miyakawa, Taisuke Mizoo,Akinobu Matsumoto,Atsushi Hijikata,Tsuyoshi Shirai,Kouta Mayanagi,Keiichi I. Nakayama
Hideo Hagihara,Hirotaka Shoji,Satoko Hattori,Giovanni Sala, Yoshihiro Takamiya, Mika Tanaka,Masafumi Ihara, Mihiro Shibutani,Izuho Hatada,Kei Hori,Mikio Hoshino,Akito Nakao,
bioRxiv (Cold Spring Harbor Laboratory) (2024)
JOURNAL OF BIOCHEMISTRYno. 2 (2024): 195-204
Oncogenepp.1-13, (2024)
Science Advancesno. 20 (2023)
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