Jung Hwa Kim

Negative Regulation of Hypoxic Responses via Induced Reptin Methylation

Lysine methylation within histones is crucial for transcriptional regulation and thus links chromatin states to biological outcomes. Although recent studies have extended lysine methylation to nonhistone proteins, underlying molecular mechanisms such as the upstream signaling cascade that induces lysine methylation and downstream target genes modulated by this modification have not been elucidated. Here, we show that Reptin, a chromatin-remodeling factor, is methylated at lysine 67 in hypoxic conditions by the methyltransferase G9a. Methylated Reptin binds to the promoters of a subset of hypoxia-responsive genes and negatively regulates transcription of these genes to modulate cellular responses to hypoxia.

RORα Attenuates Wnt/β-Catenin Signaling by PKCα-Dependent Phosphorylation in Colon Cancer

Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.

UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction.

Ubiquitin C-terminal hydrolse-L1 (UCH-L1) is a deubiquitinating enzyme (DUB) that cleaves the ubiquitin (ub) moiety from ub precursors or protein substrates. The correlation between UCH-L1 and cancer has been reported in various tissues, but the role of UCH-L1 in prostate cancer has not been thoroughly researched. Here we found that UCH-L1 is specifically highly expressed in the metastatic DU145 prostate cancer cell line, but not in the benign or weakly metastatic prostate cancer cells. To determine the role of UCH-L1 in prostate cancer metastasis, we constructed UCH-L1-knockdown DU145 and UCH-L1 or the active site mutant form of UCH-L1 (UCH-L1 C90S) expressing RWPE1 stable cells. Notably, the expression of UCH-L1 in RWPE1 cells promotes epithelial-to-mesenchymal transition (EMT), and this is an important process for cancer cell invasion and metastasis. On the contrary, knockdown of UCH-L1 in DU145 cells induces MET, the reverse program of EMT. Furthermore, the change of EMT status caused by altering the UCH-L1 level affects the migration and invasiveness of prostate cancer cells. Our results indicate that UCH-L1 promotes prostate cancer metastasis through EMT induction and UCH-L1 could be a novel diagnostic and therapeutic target for prostate cancer treatment.

SUMOylation of RORα potentiates transcriptional activation function

SUMOylation regulates a variety of cellular processes, including control of transcriptional activities of nuclear receptors. Here, we present SUMOylation of orphan nuclear receptor, RORalpha by both SUMO-1 and SUMO-2. SUMOylation of RORalpha occurred on the 240th lysine residue at the hinge region of human protein. PIAS family members, PIASxalpha, PIAS3, and PIASy, increased SUMOylation of RORalpha, whereas SENP2 specifically removed SUMO from RORalpha. SUMOylation-defective mutant form of RORalpha exhibited decreased transcriptional activity on RORalpha-responsive promoters indicating that SUMOylation may positively regulate transcriptional function of RORalpha.

Breast cancer metastasis suppressor 1 (BRMS1) is destabilized by the Cul3-SPOP E3 ubiquitin ligase complex.

Breast cancer metastasis suppressor 1 (BRMS1) suppresses metastasis without affecting primary tumorigenesis. The regulatory mechanism of BRMS1 at the protein level has not been revealed until recently. Here, we found that cullin 3 (Cul3), a component of E3 ubiquitin ligase, is a new binding partner of BRMS1 and the interaction between BRMS1 and Cul3 is mediated by the SPOP adaptor protein. Intriguingly, BRMS1 turns out to be a potent substrate that is ubiquitinated by the Cul3-SPOP complex. Knockdown of SPOP increases the level of BRMS1 protein and represses the expression of BRMS1 repressive target genes such as OPN and uPA in breast cancer cells. These results suggest that the novel regulatory mechanism of BRMS1 by Cul3-SPOP complex is important for breast cancer progression.

Bcl3-dependent stabilization of CtBP1 is crucial for the inhibition of apoptosis and tumor progression in breast cancer

B-cell lymphoma 3 (Bcl3) is a proto-oncogene upregulated in a wide range of cancers, including breast cancer. Although Bcl3 is known to promote cell proliferation and inhibit apoptosis, the molecular mechanisms underlying the proto-oncogenic function of Bcl3 have not been completely elucidated. To gain insight into the oncogenic role of Bcl3, we applied a proteomic approach, which led to the identification of C-terminal binding protein 1 (CtBP1) as a binding partner of Bcl3. A PXDLS/R motif embedded in Bcl3 was found to mediate the interaction between Bcl3 and CtBP1, which caused the stabilization of CtBP1 by blocking proteasome-dependent degradation. Apoptotic stimuli-induced degradation of CtBP1 was significantly abolished by the upregulation of Bcl3, leading to the sustained repression of pro-apoptotic gene expression and subsequent inhibition of apoptosis. Intriguingly, a strong positive correlation between the protein levels of Bcl3 and CtBP1 was detected in breast cancer patient samples. Our study reveals a novel combinatorial role for Bcl3 and CtBP1, providing an explanation for the acquisition of resistance to apoptosis in cancer cells, which is a major requirement for cancer development.

control of structure-borne noise of a plate featuring piezoceramic actuators

This paper addresses active structural acoustic control of a flexible plate using piezoelectric actuators. The analytical model of a thin plate with simply supported boundary conditions is derived from Hamiltons principle and a control model represented by the transfer function is obtained. Optimal locations of the piezoelectric actuators are found such that it minimizes the radiated sound power at the farfield. With optimally designed actuators, an controller is designed by using the loop shaping design procedure to achieve robust acoustic control of the proposed system subjected to parameter variations and external disturbances. Control performance and robustness are presented in both frequency and time domains in order to demonstrate the effectiveness of the proposed approach. In addition, the comparison between the proposed robust controller and the conventional adaptive Filtered-x LMS algorithm is undertaken.

Miscibility and rheological characteristics of biodegradable aliphatic polyester and linear low density polyethylene blends

Abstract Miscibility characteristics and rheological properties for blends of biodegradable aliphatic polyester (BDP) and linear low density polyethylene (LLDPE) were examined by both a dynamic mechanical thermal analyzer and rheometers. Eventhough this blend system was found to be immiscible from the glass transition values, the shear viscosity of the blend lies between both of the constituent components following the additivity rule with respect to the blending ratio and is fitted with Carreau model. Loss moduli are observed to be higher than storage moduli below a frequency of 10 s −1 , and storage modulus and loss modulus increase with the increase in LLDPE contents. In addition, modified Cole–Cole plots for both blend compositions at a fixed temperature and temperature at a fixed composition show that they are immiscible.

Ubiquitin C-terminal hydrolase-L3 regulates EMT process and cancer metastasis in prostate cell lines.

Ubiquitin C-terminal hydrolase-L3 (UCH-L3) is among the deubiquitinating enzymes (DUBs) that cleave ubiquitin (Ub) from Ub precursors or protein substrates. Many DUBs have been shown to participate in cancer progression in various tissues. However, the mechanism and role of UCH-L3 in carcinogenesis has largely been unknown until recently. Here we investigated the implication of UCH-L3 in prostate cancer progression. Interestingly, UCH-L3 is upregulated in normal or non-metastatic prostate cancer cells and is downregulated in metastatic prostate cancer cell lines. Notably, knockdown of UCH-L3 in normal prostate cell line RWPE1 promotes epithelial-to-mesenchymal transition (EMT), an important process for cancer cell invasion and metastasis. The induction of EMT by UCH-L3 knockdown results in an increase of cell migration and invasion. Yet, to the contrary, overexpression of UCH-L3 in highly metastatic prostate cancer cell line PC3 reverses EMT but the active site mutant UCH-L3 did not. Collectively, our findings identify UCH-L3 as a novel EMT regulator in prostate cells and highlight UCH-L3 as a potential therapeutic target for preventing metastatic prostate cancer.

Liquid crystal added electrorheological fluid

Electrorheological (ER) fluids are a class of materials whose rheological properties are controllable via the application of an external electric field. Without the presence of an electric field, the ER fluid exhibits Newtonian fluid behavior. However, when an electric field is applied to an ER fluid, its rheological response demonstrates Bingham characteristics. Since a typical ER fluid consists of a suspension of fine dielectric particles in a dielectric liquid, this ER behavior is considered to stem from polarization of the particles and the resultant structural change [1–3]. In order to obtain the polarization of the suspended particles, the dielectric constants of both the particles and the liquid medium must be different with the dielectric constant of the particles being typically higher than that of liquid. When an electric field is applied, a mutually interacting force occurs among these polarized particles, which form chains and aggregate to form thick columns bridging the two electrodes [4]. Increasing the ER effect is a natural way to improve the yield stress since the shear stress is related to the rate of change for the electric energy density with respect to the shear deformation. This rate of change depends mainly on the particle structures formed in an external electric field and the energy density of the ER fluids. When the structures are the same, the energy densities increase at a given electric field either by a increasing the mismatch between the dielectric constants of the particle and the carrier fluids or additives [5]. Although there exist reports of many particledispersed ER fluids, their practical utilization has been limited due to particle sedimentation, aggregation or solidification; particle or electrode abrasion; poor durability; and temperature dependence [6]. Low molar mass liquid crystals (LC) [7], lyotropic polymeric liquid crystals [8], and ferroelectric polymer solutions [9] have been proposed as alternative materials to resolve these problems. Compared to wet-base ER materials, in which the particles contain small amounts of moisture, various anhydrous systems, including zeolite [10] and conducting polymers such as polyaniline and its derivatives [11–14], poly(acene guinone) radicals [15], poly(p-phenylene) [16], polypyrrole [17], polymer/clay nanocomposites [18–20], and phosphate cellulose [21],