Authorship：Lead author   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Immune checkpoint inhibitor (ICI) therapy has caused a paradigm shift in cancer therapeutic strategy. However, this therapy only benefits a subset of patients. The difference in responses to ICIs is believed to be dependent on cancer type and its tumor microenvironment (TME). The TME is favorable for cancer progression and metastasis and can also help cancer cells to evade immune attacks. To improve the response to ICIs, it is crucial to understand the mechanism of how the TME is maintained. Protein arginine methyltransferase 5 (PRMT5) di-methylates arginine residues in its substrates and has essential roles in the epigenetic regulation of gene expression, signal transduction, and the fidelity of mRNA splicing. Through these functions, PRMT5 can support cancer cell immune evasion. PRMT5 is necessary for regulatory T cell (Treg) functions and promotes cancer stemness and the epithelial–mesenchymal transition. Specific factors in the TME can help recruit Tregs, tumor-associated macrophages, and myeloid-derived suppressor cells into tumors. In addition, PRMT5 suppresses antigen presentation and the production of interferon and chemokines, which are necessary to recruit T cells into tumors. Overall, PRMT5 supports an immunosuppressive TME. Therefore, PRMT5 inhibition would help recover the immune cycle and enable the immune system-mediated elimination of cancer cells.

DOI： 10.3390/genes14030678

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MDPI AG  

Kawasaki disease (KD) is an acute inflammatory syndrome of unknown etiology that is complicated by cardiovascular sequelae. Chronic inflammation (vasculitis) due to KD might cause vascular cellular senescence and vascular endothelial cell damage, and is a potential cause of atherosclerosis in young adults. This study examined the effect of KD and HMG-CoA inhibitors (statins) on vascular cellular senescence and vascular endothelial cells. Candida albicans water-soluble fraction (CAWS) was administered intraperitoneally to 5-week-old male apolipoprotein E-deficient (Apo E-/-) mice to induce KD-like vasculitis. The mice were then divided into three groups: control, CAWS, and CAWS+statin groups. Ten weeks after injection, the mice were sacrificed and whole aortic tissue specimens were collected. Endothelial nitric oxide synthase (eNOS) expression in the ascending aortic intima epithelium was evaluated using immunostaining. In addition, eNOS expression and levels of cellular senescence markers were measured in RNA and proteins extracted from whole aortic tissue. KD-like vasculitis impaired vascular endothelial cells that produce eNOS, which maintains vascular homeostasis, and promoted macrophage infiltration into the tissue. Statins also restored vascular endothelial cell function by promoting eNOS expression. Statins may be used to prevent secondary cardiovascular events during the chronic phase of KD.

DOI： 10.3390/ijms232416108

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Language：English   Publishing type：Research paper (scientific journal)  

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Language：English   Publishing type：Research paper (scientific journal)  

DOI： 10.3390/bioengineering7010018

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Authorship：Lead author   Language：English   Publisher：MDPI Multidisciplinary Digital Publishing Institute  

The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field.

DOI： 10.3390/jdb5040012

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Other Link： http://orcid.org/0000-0003-3894-494X

Authorship：Lead author   Language：English   Publisher：HINDAWI LTD  

Lung cancer is the most common cause of cancer-related death worldwide and is classified into small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Several gene mutations that contribute to aberrant cell proliferation have been identified in lung adenocarcinoma, a part of NSCLC. Various anticancer drugs that target these mutated molecules have been developed for NSCLC treatment. However, although molecularly targeted drugs are initially effective for patients, the 5-year survival rate remains low because of tumor relapse. Therefore, more effective drugs for lung cancer treatment should be developed. The hedgehog (HH) signaling pathway contributes to organ development and stem cell maintenance, and aberrant activation of this signaling pathway is observed in various cancers including lung cancer. In lung cancer, HH signaling pathway upregulates cancer cell proliferation and maintains cancer stem cells as well as cancer-associated fibroblasts (CAFs). Furthermore, physical contact between CAFs and NSCLC cells induces HH signaling pathway activation in NSCLC cells to enhance their metastatic potential. Therefore, HH signaling pathway inhibitors could be a useful option for lung cancer therapy.

DOI： 10.1155/2016/7969286

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

Tob belongs to the anti-proliferative Tob/BTG family. The level of Tob throughout the cell cycle is regulated by the SCF (Skp1/Cullin/F-box protein) Skp2 ubiquitin ligase (E3) complex. Here, we show that Coronin7 (CRN7) is also involved in Tob degradation. We identified CRN7 as a Tob-interacting molecule. A sequence containing two of the six WD motifs in the middle of CRN7 was responsible for the interaction. CRN7 enhanced the polyubiquitination of Tob in vitro, and overexpression of CRN7 promoted proteasome-dependent degradation of Tob. Furthermore, CRN7 interacted with Cullin1 and Roc1 to form a novel SCF-like E3 complex, suggesting that Tob protein is regulated by multiple ubiquitination machineries.
Structured summary:
Cullin1 physically interacts with CRN7:shown by anti tag coimmunoprecipitation (view interaction)
Roc1 physically interacts with CRN7:shown by anti tag coimmunoprecipitation (view interaction)
CRN7 physically interacts with Tob1:shown by anti tag coimmunoprecipitation (view interaction)
CDC34 physically interacts with CRN7:shown by anti tag coimmunoprecipitation (view interaction)
Tob1 and CRN7 colocalize:shown by fluorescence microscopy (view interaction)
Elongin B physically interacts with CRN7:shown by anti tag coimmunoprecipitation (view interaction)
Elongin C physically interacts with CRN7:shown by anti tag coimmunoprecipitation (view interaction)
Tob1 physically interacts with CRN7:shown by two hybrid (view interaction) (C) 2010 Federation of European Biochemical Societies. Published by Elsevier B. V. All rights reserved.

DOI： 10.1016/j.febslet.2010.11.049

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Language：English   Publishing type：Research paper (scientific journal)  

Enhanced glycolysis is important for oncogenesis and for the survival and proliferation of cancer cells in the tumor microenvironment. Recent studies have also shown that proinflammatory cytokine signaling, such as that mediated by nuclear factor κB and signal transducer and activator of transcription 3 (STAT3), is important for the generation of inflammation-associated tumors. However, the link between inflammation and enhanced glycolysis has not been identified. In the present study, we found that the proinflammatory cytokine interleukin (IL)-6 enhanced glycolysis in mouse embryonic fibroblasts and human cell lines. Moreover, STAT3 activated by IL-6 enhanced the expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase-3 (PFKFB3). Ectopic expression of PFKFB3 enhanced glycolysis, suggesting that the IL-6-STAT3 pathway enhances glycolysis through the induction of these enzymes. Our findings may provide a novel mechanism for inflammation-associated oncogenesis.

DOI： 10.1272/jnms.77.97

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Authorship：Lead author   Language：Japanese   Publishing type：Research paper (scientific journal)  

DOI： 10.11477/mf.2425100944

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Publisher：Faculty of 1000, Ltd.  

DOI： 10.3410/f.1109006.566173

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The Wnt signaling pathway is essential for embryonic development and carcinogenesis. Upon Wnt stimulation, beta-catenin is stabilized and associates with T-cell factor or lymphoid enhancing factor, thereby activating transcription of target genes. In the absence of Wnt stimulation, the level of beta-catenin is reduced via glycogen synthase kinase (GSK)-beta b-mediated phosphorylation and subsequent proteasome-dependent degradation. Here, we report the identification of Ajuba as a negative regulator of the Wnt signaling pathway. Ajuba is a member of LIM domain-containing proteins that contribute to cell fate determination and regulate cell proliferation and differentiation. We found that enforced expression of Ajuba destabilized beta-catenin and suppressed target gene expression. Ajuba promoted GSK-3 beta-mediated phosphorylation of beta-catenin by reinforcing the association between beta-catenin and GSK-3 beta. Furthermore, Wnt stimulation induced both accumulation of beta-catenin and destabilization of Ajuba. Our findings suggest that Ajuba is important for regulation of the Wnt signaling pathway.

DOI： 10.1038/sj.onc.1210644

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：COMPANY OF BIOLOGISTS LTD  

Focal adhesion protein ZRP-1/TRIP6 has been implicated in actin reorganization and cell motility. The role of ZRP-1, however, remained obscure because previously reported data are often conflicting one another. In the present study, we examined roles of ZRP-1 in HeLa cells. ZRP-1 is localized to the cell-cell contact sites as well as to cell-matrix contact sites in HeLa cells. RNA-interference-mediated depletion of ZRP-1 from HeLa cells revealed that ZRP-1 is essential not only for the formation of stress fibers and assembly of mature focal adhesions, but also for the actin reorganization at cell-cell contact sites and for correct cell-cell adhesion and, thus, for collective cell migration. Impairment of focal adhesions and stress fibers caused by ZRP-1 depletion has been associated with reduced tyrosine phosphorylation of FAK. However, maturation of focal adhesions could not be recovered by expression of active FAK. Interestingly, stress fibers in ZRP-1-depleted cells were ameliorated by exogenous expression of RhoA. We also found that total Rac1 activity is elevated in ZRP-1-depleted cells, resulting in abnormal burst of actin polymerization and dynamic membrane protrusions. Taken together, we conclude that that ZRP-1 plays a crucial role in coupling the cell-matrix/cell-cell-contact signals with Rho GTPase-mediated actin remodeling by localizing at cell-matrix and cell-cell contact sites.

DOI： 10.1242/jcs.03477

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Authorship：Lead author   Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

LATS2 is a human homolog of Drosaphila tumor suppressor lats/warts, and encodes a mitotic kinase whose physiological roles remain to be elucidated. We performed yeast two-hybrid screening and identified a LIM protein Ajuba, as a binding partner of LATS2. LATS2 was localized to the centrosomes throughout the cell cycle and was associated with Ajuba during mitosis, contributing to latter's mitotic phosphorylation. Depletion of LATS2 or Ajuba impaired centrosomal accumulation of gamma-tubulin and spindle formation at the onset of mitosis, suggesting that the LATS2-Ajuba complex regulates organization of the spindle apparatus through recruitment of gamma-tubulin to the centrosome. (c) 2006 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.

DOI： 10.1016/j.febslet.2005.12.096

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

By means of successive heparin-affinity and glycyrrhizin (GL)-affinity column chromatographies (HPLC), a 55 kDa GL-binding protein (gp55) was purified to apparent homogeneity from the Superdex P-I fraction of Habu snake venom. This gp55 was identified as an apoxin I-like protein, because (i) its 20 N-terminal amino acid residues (AHDRNPLEEYFRETDYEEFL) are 95% identical with the corresponding sequence of apoxin I (apoptosis-inducing factor, approx. 55 kDa) in the venom of the western diamondback rattlesnake; and (ii) L-amino acid oxidase (LAO) activity of gp55 is detected when incubated with L-leucine, but not with D-leucine. GL inhibited the LAO activity of gp55 in a dose-dependent manner, but had no effect on the activity of a 65 kDa LAO also purified from Habit snake venom. In addition, GL reduced the ability of gp55 to induce the hemolysis of sheep red blood cells. These results suggest that GL is a potent inhibitor of apoxin I-like proteins in harmful snake venoms.

DOI： 10.1248/bpb.21.924

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

By means of glycyrrhizin (GL)-affinity and Mono S column chromatographies (HPLC), at least four GL-binding proteins (p25, p17, p15-1 and p15-2) in the two Superdex fractions (P-II and P-III fractions) from Habu snake venom were selectively purified, Bg determination of their N-terminal partial amino acid sequences, a metalloprotease (p25) and three GL-binding phospholipases Az (gbPLA(2)s) [PA2Y (p17), PA21 (p15-1) and PA2B (p15-2)] were identified. PA2B (lysine-49 PLA(2)) was found to be the most sensitive to GL because (i) it strongly bound to a GL-affinity column; and (ii) its enzyme activity was selectively inhibited by low dose (ID50=approx. 1.5 mu M) of GL, hut not by GA. Furthermore, these three gbPLA(2)s were phosphorylated by casein kinase II (CK-II) in vitro and GL inhibited the CK-II-mediated stimulation of their enzyme activities in vitro.

DOI： 10.1248/bpb.21.574

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Language：Japanese   Publisher：(公社)日本生化学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：Japanese   Publisher：日本癌学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPAN SOC CELL BIOLOGY  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：JAPAN SOC CELL BIOLOGY  

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