Novel Functions of Prolyl Isomerase Pin1(Recent Topics of the Agricultunal Biological Science in Tohoku University)

We have studied the novel functions of peptidyl prolyl cis/trans isomerase Pin1 that specifically binds the phosphorylated Ser/Thr-Pro protein motifs and catalyzes the cis/trans isomerization of the peptide bond. Accumulating studies have revealed that Pin1 isomerase activity is regulated by its post-translational modifications, including phosphorylation and oxidation. Various transcription factors and regulators have been identified as substrates for Pin1. It enhances AP-l activity via isomerization of both c-Jun and c-Fos for cellular proliferation and stabilizes the oncosuppressors p53 and p73 against DNA damage at the checkpoint. We demonstrated the association between the intracellular form of Notchl (NIC) and Pin1 by analyzing Pin1/p53 double knockout mice. Pin1 also regulates the posttranscriptional level of some cytokines, associated with asthma, that possess 3\u27 untranslated region AU-rich elements (ARE) via interaction with AUF-1, the nucleoprotein in the ARE-binding complex. Pin1 has been identified as the molecular partner of tau and amyloid precursor protein (APP), the key factors of Alzheimer\u27s disease (AD). It interacts with the phosphorylated Thr-231 of tau and regulates its activity to bind microtubules. It further interacts with the phosphorylated Thr-668 of APP and affects its metabolism. Thus, Pin1 is probably involved in the pathogenesis of human pathologies, including cancer, asthma and AD, presenting an attractive target for future therapeutical drugs

Prolyl Isomerase Pin1 Protects Mice from Endotoxin Shock

Prolyl isomerase Pin1 may be involved in innate immunity against microbial infection, but the mechanism how Pin1 controls the innate immunity is poorly understood.Injection of lipopolysaccharide (LPS) into the mice induces inflammatory pulmonary disorder and sometimes the serious damages lead to death. Comparing to the wild-type (WT) mice, the Pin1⁻/⁻ mice showed more serious damages in lung and the lower survival rate after the LPS injection. We compared the levels of typical inflammatory cytokines. Pin1⁻/⁻ mice overreacted to the LPS injection to produce inflammatory cytokines, especially IL-6 more than WT mice. We showed that Pin1 binds phosphorylated PU.1 and they localize together in a nucleus. These results suggest that Pin1 controls the transcriptional activity of PU.1 and suppresses overreaction of macrophage that causes serious damages in lung.Pin1 may protect the mice from serious inflammation by LPS injection by attenuating the increase of IL-6 transcription of the mouse macrophages

Prolyl Isomerase Pin1 Regulates Mouse Embryonic Fibroblast Differentiation into Adipose Cells

isomerase, Pin1, regulates insulin signal transduction. Pin1 reduces responses to insulin stimulation by binding CRTC2 (CREB-regulated transcriptional co-activator 2) and PPARγ (peroxisome prolifereator- activated receptor γ), but conversely enhances insulin signaling by binding IRS-1 (insulin receptor substrate-1), Akt kinase, and Smad3. Therefore, it is still unclear whether Pin1 inhibits or enhances adipose cell differentiation. mice was restored by increasing expression of Pin1. We found that Pin1 binds to phosphoThr172- and phosphoSer271-Pro sites in CREB suppress the activity in COS-7 cells.Pin1 enhanced the uptake of triglycerides and the differentiation of MEF cells into adipose cells in response to insulin stimulation. Results of this study suggest that Pin1 down-regulation could be a potential approach in obesity-related dysfunctions, such as high blood pressure, diabetes, non-alcoholic steatohepatitis

Involvement of crosstalk between Oct4 and Meis1a in neural cell fate decision.

Oct4 plays a critical role both in maintaining pluripotency and the cell fate decision of embryonic stem (ES) cells. Nonetheless, in the determination of the neuroectoderm (NE) from ES cells, the detailed regulation mechanism of the Oct4 gene expression is poorly understood. Here, we report that crosstalk between Oct4 and Meis1a, a Pbx-related homeobox protein, is required for neural differentiation of mouse P19 embryonic carcinoma (EC) cells induced by retinoic acid (RA). During neural differentiation, Oct4 expression was transiently enhanced during 6-12 h of RA addition and subsequently disappeared within 48 h. Coinciding with up-regulation of Oct4 expression, the induction of Meis1a expression was initiated and reached a plateau at 48 h, suggesting that transiently induced Oct4 activates Meis1a expression and the up-regulated Meis1a then suppresses Oct4 expression. Chromatin immunoprecipitation (ChIP) and luciferase reporter analysis showed that Oct4 enhanced Meis1a expression via direct binding to the Meis1 promoter accompanying histone H3 acetylation and appearance of 5-hydoxymethylcytosine (5hmC), while Meis1a suppressed Oct4 expression via direct association with the Oct4 promoter together with histone deacetylase 1 (HDAC1). Furthermore, ectopic Meis1a expression promoted neural differentiation via formation of large neurospheres that expressed Nestin, GLAST, BLBP and Sox1 as neural stem cell (NSC)/neural progenitor markers, whereas its down-regulation generated small neurospheres and repressed neural differentiation. Thus, these results imply that crosstalk between Oct4 and Meis1a on mutual gene expressions is essential for the determination of NE from EC cells

Visualizing Liquid-Gas Two-Phase Flow

We visualize liquid-gas two-phase flow by explicitly expressing morphogenesis of interfaces between phases. Our fundamental idea is to describe interfaces using implicit surfaces. We controlled the motion of primitives of implicit surfaces by the way similar to molecular dynamics. This method enables simulating coalescence and disintegration of vapor bubbles in two-phase flow. We make some animations, showing various flow patterns from the results of numerical simulation of two-phase flow. Also we develop a global illumination model appropriate to make realistic images of two-phase flow. 1 Introduction Flow visualization plays a fundamental role in analysis of phenomena in a wide variety of scientific fields. Most visualization so far has concentrated on single-phase flow, and distributions of flow variables, such as velocity, pressure and temperature, have been visualized using the results from fluid flow calculations. This paper is concerned with two-phase flow which is important in..