Effect of length of hydroxyalkyl groups in the clay modifier on the properties of thermoplastic polyurethane/clay nanocomposites

Kim, Wantae,Chung, Dae-won,Kim, Jeong Ho Wiley Subscription Services, Inc., A Wiley Company 2008 Journal of applied polymer science Vol.110 No.5

<P>Polyether- and polyester-based thermoplastic polyurethane (TPU) nanocomposites containing the montmorillonite modified with quaternary ammonium salts having a relatively long hydroxyalkyl branch (MMT-OH) were prepared via solution mixing. Quaternary ammonium salts with dimethyl, octyl, hydroxyundecyl branches were synthesized by the addition reaction of dimethyloctylamine and 11-bromo-1-undecanol and were used for the preparation of MMT-OH. In this MMT-OH clay, hydroxyl groups are located at the outer end of the relatively long undecyl branch, which may make the hydroxyl groups more exposed to the matrix polymers compared to the clays with the modifiers having shorter hydroxyalkyl chain such as C30B. Actually, more hydroxyl groups in MMT-OH's are thought to be exposed outside the modified clay, since MMT-OH's were observed to be somewhat dispersed in water, while clays with shorter alkyl chains were not. From XRD and TEM results, the silicate layers of MMT-OH were shown to be very well dispersed in ether-TPU and ester-TPU nanocomposites prepared from dimethyl acetamide solution. In the case of ester-TPU nanocomposites, much better clay dispersion was observed for nanocomposites containing MMT-OH than the ones with C30B in the TEM images. The tensile properties measurement showed the similar trend. Although MMT-OH has only one hydroxyl group while C30B has two, above results of better tensile properties and water dispersibility of MMT-OH than C30B having two hydroxyls indicate that the position of hydroxyls may be a important factor in determining the properties of TPU/clay nanocomposites. Fourier transform infrared spectroscopy analyses showed that the long hydroxyalkyl chain modifiers may provide more hydrogen bonding sites than short hydroxyalkyl chain modifiers. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008</P>

The history and regulatory mechanism of the Hippo pathway

( Wantae Kim ),( Eek-hoon Jho ) 생화학분자생물학회(구 한국생화학분자생물학회) 2018 BMB Reports Vol.51 No.3

How the organ size is adjusted to the proper size during development and how organs know that they reach the original size during regeneration remain long-standing questions. Based on studies using multiple model organisms and approaches for over 20 years, a consensus has been established that the Hippo pathway plays crucial roles in controlling organ size and maintaining tissue homeostasis. Given the significance of these processes, the dysregulation of the Hippo pathway has also implicated various diseases, such as tissue degeneration and cancer. By regulating the downstream transcriptional coactivators YAP and TAZ, the Hippo pathway coordinates cell proliferation and apoptosis in response to a variety of signals including cell contact inhibition, polarity, mechanical sensation and soluble factors. Since the core components and their functions of the Hippo pathway are evolutionarily conserved, this pathway serves as a global regulator of organ size control. Therefore, further investigation of the regulatory mechanisms will provide physiological insights to better understand tissue homeostasis. In this review, the historical developments and current understandings of the regulatory mechanism of Hippo signaling pathway are discussed. [BMB Reports 2018; 51(3): 106-118]

Interacting network of Hippo, Wnt/β-catenin and Notch signaling represses liver tumor formation

( Wantae Kim ),( Sanjoy Kumar Khan ),( Yingzi Yang ) 생화학분자생물학회(구 한국생화학분자생물학회) 2017 BMB Reports Vol.50 No.1

Acquiring a selective growth advantage by breaking the proliferation barrier established by gatekeeper genes is a centrally important event in tumor formation. Removal of the mammalian Hippo kinase Mst1 and Mst2 in hepatocytes leads to rapid hepatocellular carcinoma (HCC) formation, indicating that the Hippo signaling pathway is a critical gatekeeper that restrains abnormal growth in hepatocytes. By rigorous genetic approaches, we identified an interacting network of the Hippo, Wnt/β-catenin and Notch signaling pathways that control organ size and HCC development. We found that in hepatocytes, the loss of Mst1/2 leads to the activation of Notch signaling, which forms a positive feedback loop with Yap/Taz (transcription factors controlled by Mst1/2). This positive feedback loop results in severe liver enlargement and rapid HCC formation. Blocking the Yap/Taz-Notch positive feedback loop by Notch inhibition in vivo significantly reduced the Yap/Taz activities, hepatocyte proliferation and tumor formation. Furthermore, we uncovered a surprising inhibitory role of Wnt/β-catenin signaling to Yap/Taz activities, which are important in tumor initiation. Genetic removal of β-catenin in the liver of the Mst1/2 mutants significantly accelerates tumoriogenesis. Therefore, Wnt/β-catenin signaling, known for its oncogenic property, exerts an unexpected function in restricting Yap/Taz and Notch activities in HCC initiation. The molecular interplay between the three signaling pathways identified in our study provides new insights in developing novel therapeutic strategies to treat liver tumors. [BMB Reports 2017; 50(1): 1-2]

Hippo signaling is intrinsically regulated during cell cycle progression by APC/C^Cdh1

Kim, Wantae,Cho, Yong Suk,Wang, Xiaohui,Park, Ogyi,Ma, Xueyan,Kim, Hanjun,Gan, Wenjian,Jho, Eek-hoon,Cha, Boksik,Jeung, Yun-ji,Zhang, Lei,Gao, Bin,Wei, Wenyi,Jiang, Jin,Chung, Kyung-Sook,Yang, Yingzi National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.19

<P><B>Significance</B></P><P>The Hippo signaling pathway is evolutionarily conserved in the animal kingdom and plays essential roles in regulating tissue growth during development and regeneration. We have identified APC/C<SUP>Cdh1</SUP>, a core component of cell cycle control machinery, as an evolutionarily conserved and previously unknown regulator of large tumor suppressor (LATS) kinases, which critically inhibit the YAP/TAZ transcription factors in transducing Hippo signaling. Our results suggest a model that APC/C<SUP>Cdh1</SUP> destabilizes LATS1/2 kinases in G1 phase of the cell cycle, leading to increased YAP/TAZ activities that promote G1/S transition by upregulating downstream gene expression, including <I>E2F1</I>. Our findings have important implications for a link between cell proliferation and LATS-regulated YAP/TAZ activities.</P><P>The Hippo-YAP/TAZ signaling pathway plays a pivotal role in growth control during development and regeneration and its dysregulation is widely implicated in various cancers. To further understand the cellular and molecular mechanisms underlying Hippo signaling regulation, we have found that activities of core Hippo signaling components, large tumor suppressor (LATS) kinases and YAP/TAZ transcription factors, oscillate during mitotic cell cycle. We further identified that the anaphase-promoting complex/cyclosome (APC/C)<SUP>Cdh1</SUP> E3 ubiquitin ligase complex, which plays a key role governing eukaryotic cell cycle progression, intrinsically regulates Hippo signaling activities. CDH1 recognizes LATS kinases to promote their degradation and, hence, YAP/TAZ regulation by LATS phosphorylation is under cell cycle control. As a result, YAP/TAZ activities peak in G1 phase. Furthermore, we show in <I>Drosophila</I> eye and wing development that Cdh1 is required in vivo to regulate the LATS homolog Warts with a conserved mechanism. Cdh1 reduction increased Warts levels, which resulted in reduction of the eye and wing sizes in a Yorkie dependent manner. Therefore, LATS degradation by APC/C<SUP>Cdh1</SUP> represents a previously unappreciated and evolutionarily conserved layer of Hippo signaling regulation.</P>

Sonochemical Synthesis of Zeolite A from Metakaolinite in NaOH Solution

Kim, Wantae,Choi, Doyoung,Kim, Sangbae The Japan Institute of Metals 2010 MATERIALS TRANSACTIONS Vol.51 No.9

<P>Sonochemical synthesis of zeolite A has been conducted by ultrasonic irradiation of mixtures of metakaolinite and NaOH solution. The hydrothermal synthesis at conventional synthesis conditions was undertaken to determine the sonochemical reliability. The enhancement of nucleation and crystallization rate of zeolite A was achieved by ultrasound. In the ultrasonic field, zeolite A once formed in the suspension has been converted into hydroxysodalite and losod as sonicating proceeded. Comparing the results with those of conventional methods, this heterogeneous reaction was particularly accelerated by ultrasound, leading to improved reactivity of solid reactant through intensive mixing. The use of ultrasound enables us to prepare well-dispersed fine zeolite A particles with mean particle size of around 1 μm. The cation exchange capacity values of the products increased as the synthesis reaction for zeolite A proceeded. The high solid concentration in the suspension, however, hindered the ultrasound from intense agitating, resulting in the decrease of zeolite A yield.</P>

Wnt/β-catenin signalling: from plasma membrane to nucleus.

Kim, Wantae,Kim, Minseong,Jho, Eek-hoon Biochemical Society 2013 Biochemical journal Vol.450 No.1

<P>Wnt/β-catenin signalling plays essential roles in embryonic development as well as tissue homoeostasis in adults. Thus abnormal regulation of Wnt/β-catenin signalling is linked to a variety of human diseases, including cancer, osteoporosis and Alzheimer's disease. Owing to the importance of Wnt signalling in a wide range of biological fields, a better understanding of its precise mechanisms could provide fundamental insights for therapeutic applications. Although many studies have investigated the regulation of Wnt/β-catenin signalling, our knowledge remains insufficient due to the complexity and diversity of Wnt signalling. It is generally accepted that the identification of novel regulators and their functions is a prerequisite to fully elucidating the regulation of Wnt/β-catenin signalling. Recently, several novel modulators of Wnt signalling have been determined through multiple genetic and proteomic approaches. In the present review, we discuss the mechanistic regulation of Wnt/β-catenin signalling by focusing on the roles of these novel regulators.</P>

TPX2 prompts mitotic survival via the induction of BCL2L1 through YAP1 protein stabilization in human embryonic stem cells

Kim Yun-Jeong,Go Young-Hyun,Jeong Ho-Chang,Kwon Eun-Ji,Kim Seong-Min,Cheong Hyun Sub,Kim Wantae,Shin Hyoung Doo,Lee Haeseung,Cha Hyuk-Jin 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Genetic alterations have been reported for decades in most human embryonic stem cells (hESCs). Survival advantage, a typical trait acquired during long-term in vitro culture, results from the induction of BCL2L1 upon frequent copy number variation (CNV) at locus 20q11.21 and is one of the strongest candidates associated with genetic alterations that occur via escape from mitotic stress. However, the underlying mechanisms for BCL2L1 induction remain unknown. Furthermore, abnormal mitosis and the survival advantage that frequently occur in late passage are associated with the expression of BCL2L1, which is in locus 20q11.21. In this study, we demonstrated that the expression of TPX2, a gene located in 20q11.21, led to BCL2L1 induction and consequent survival traits under mitotic stress in isogenic pairs of hESCs and human induced pluripotent stem cells (iPSCs) with normal and 20q11.21 CNVs. High Aurora A kinase activity by TPX2 stabilized the YAP1 protein to induce YAP1-dependent BCL2L1 expression. A chemical inhibitor of Aurora A kinase and knockdown of YAP/TAZ significantly abrogated the high tolerance to mitotic stress through BCL2L1 suppression. These results suggest that the collective expression of TPX2 and BCL2L1 from CNV at loci 20q11.21 and a consequent increase in YAP1 signaling promote genome instability during long-term in vitro hESC culture.

Hippo signaling interactions with Wnt/β-catenin and Notch signaling repress liver tumorigenesis

Kim, Wantae,Khan, Sanjoy Kumar,Gvozdenovic-Jeremic, Jelena,Kim, Youngeun,Dahlman, Jason,Kim, Hanjun,Park, Ogyi,Ishitani, Tohru,Jho, Eek-hoon,Gao, Bin,Yang, Yingzi American Society for Clinical Investigation 2017 The Journal of clinical investigation Vol.127 No.1

<P>Malignant tumors develop through multiple steps of initiation and progression, and tumor initiation is of singular importance in tumor prevention, diagnosis, and treatment. However, the molecular mechanism whereby a signaling network of interacting pathways restrains proliferation in normal cells and prevents tumor initiation is still poorly understood. Here, we have reported that the Hippo, Wnt/beta-catenin, and Notch pathways form an interacting network to maintain liver size and suppress hepatocellular carcinoma (HCC). Ablation of the mammalian Hippo kinases Mst1 and Mst2 in liver led to rapid HCC formation and activated Yes-associated protein/WW domain containing transcription regulator 1 (YAP/TAZ), STAT3, Wnt/beta-catenin, and Notch signaling. Previous work has shown that abnormal activation of these downstream pathways can lead to HCC. Rigorous genetic experiments revealed that Notch signaling forms a positive feedback loop with the Hippo signaling effector YAP/TAZ to promote severe hepatomegaly and rapid HCC initiation and progression. Surprisingly, we found that Wnt/beta-catenin signaling activation suppressed HCC formation by inhibiting the positive feedback loop between YAP/TAZ and Notch signaling. Furthermore, we found that STAT3 in hepatocytes is dispensable for HCC formation when mammalian sterile 20-like kinase 1 and 2 (Mst1 and Mst2) were removed. The molecular network we have identified provides insights into HCC molecular classifications and therapeutic developments for the treatment of liver tumors caused by distinct genetic mutations.</P>

Dual Function of Wnt Signaling during Neuronal Differentiation of Mouse Embryonic Stem Cells

Kim, Hanjun,Kim, Sewoon,Song, Yonghee,Kim, Wantae,Ying, Qi-Long,Jho, Eek-hoon Hindawi Publishing Corporation 2015 Stem cells international Vol.2015 No.-

<P>Activation of Wnt signaling enhances self-renewal of mouse embryonic and neural stem/progenitor cells. In contrast, undifferentiated ES cells show a very low level of endogenous Wnt signaling, and ectopic activation of Wnt signaling has been shown to block neuronal differentiation. Therefore, it remains unclear whether or not endogenous Wnt/<I>β</I>-catenin signaling is necessary for self-renewal or neuronal differentiation of ES cells. To investigate this, we examined the expression profiles of Wnt signaling components. Expression levels of Wnts known to induce <I>β</I>-catenin were very low in undifferentiated ES cells. Stable ES cell lines which can monitor endogenous activity of Wnt/<I>β</I>-catenin signaling suggest that Wnt signaling was very low in undifferentiated ES cells, whereas it increased during embryonic body formation or neuronal differentiation. Interestingly, application of small molecules which can positively (BIO, GSK3<I>β</I> inhibitor) or negatively (IWR-1-endo, Axin stabilizer) control Wnt/<I>β</I>-catenin signaling suggests that activation of that signaling at different time periods had differential effects on neuronal differentiation of 46C ES cells. Further, ChIP analysis suggested that <I>β</I>-catenin/TCF1 complex directly regulated the expression of <I>Sox1</I> during neuronal differentiation. Overall, our data suggest that Wnt/<I>β</I>-catenin signaling plays differential roles at different time points of neuronal differentiation.</P>

Deubiquitinase YOD1 potentiates YAP/TAZ activities through enhancing ITCH stability

Kim, Youngeun,Kim, Wantae,Song, Yonghee,Kim, Jeong-Rae,Cho, Kyungjoo,Moon, Hyuk,Ro, Simon Weonsang,Seo, Eunjeong,Ryu, Yeon-Mi,Myung, Seung-Jae,Jho, Eek-Hoon National Academy of Sciences 2017 Proceedings of the National Academy of Sciences Vol.114 No.18

<P>Hippo signaling controls the expression of genes regulating cell proliferation and survival and organ size. The regulation of core components in the Hippo pathway by phosphorylation has been extensively investigated, but the roles of ubiquitination-deubiquitination processes are largely unknown. To identify deubiquitinase(s) that regulates Hippo signaling, we performed unbiased siRNA screening and found that YOD1 controls biological responses mediated by YAP/TAZ. Mechanistically, YOD1 deubiquitinates ITCH, an E3 ligase of LATS, and enhances the stability of ITCH, which leads to reduced levels of LATS and a subsequent increase in the YAP/TAZ level. Furthermore, we show that the miR-21-mediated regulation of YOD1 is responsible for the cell-density-dependent changes in YAP/TAZ levels. Using a transgenic mouse model, we demonstrate that the inducible expression of YOD1 enhances the proliferation of hepatocytes and leads to hepatomegaly in a YAP/TAZ-activity-dependent manner. Moreover, we find a strong correlation between YOD1 and YAP expression in liver cancer patients. Overall, our data strongly suggest that YOD1 is a regulator of the Hippo pathway and would be a therapeutic target to treat liver cancer.</P>