| Co-Investigator(Kenkyū-buntansha) |
FUKUMOTO Manabu Tohoku University, Institute of Development, Aging and Cancer, Professor, 加齢医学研究所, 教授 (60156809)
UCHIDA Chiyoko Ibaraki University, Health Center, Associate Professor, 保健管理センター, 助教授 (80312776)
FUJIMORI Fumihiro Tokyo Science University, Engineering, Assistant Professor, 基礎工学部, 助手 (50318226)
|
|---|
| Research Abstract |
The phosphorylation of proteins is a vital biological signal in cells, critical for processes such as signal transduction, cell cycle progression, and apoptosis. It is well documented that the addition of a phosphate group can cause a protein to assume a different biological role from its unphosphorylated form. However, what is not understood is the structural basis for the observed functional changes as a result of phosphorylation. Peptidyl prolyl cis-trans isomerase (PPIase) catalyzes the cis-trans isomerization of prolyl peptide bonds, and PPIase activity is required for the assembly, folding, and transport of cellular proteins. Pin1 is a PPIase from the pavilion family chat may be particularly important for cell signaling because, in addition to its PPIase domain, it has a WW domain at its N terminus that recognizes and interacts with phosphoserine (pSer) or phosphothreonine (pThr)-proline motifs in several proteins. Specifically, Pin1 binds to pSer/pThr-Pro sequences and isomerizes pSer/pThr-Pro bonds, altering the protein conformation in a phosphorylation-dependent manner and/or promoting protein dephosphorylation. This strongly supports a role for Pin1 as an integral component of the change in function of phosphorylated proteins. In mice, a knockout of the Pin1 gene resulted in viable offspring, albeit with detectable phenotypes, such as such as retinal atrophy, impaired mammary epithelial expansion during pregnancy, infertile and age-dependent neurodegeneration. The analysis of the cells prepared from Pin1-KO mice showed that Pin1 regulates the level and the activities of p53 positively and Pin1 controls c-myc degradation. We also screened chemical library and identified a series of inhibitors. They were used to show that Pin1 is important for cell cycle progression.
|
