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H. Erikson 대한전자공학회 1998 대한전자공학회 심포지엄 논문집 Vol.3 No.-

Polo-Like Kinase 1 Depletion Induces DNA Damage in Early S Prior to Caspase Activation

Yim, Hyungshin,Erikson, Raymond L. American Society for Microbiology 2009 Molecular and cellular biology Vol.29 No.10

<B>ABSTRACT</B><P>Polo-like kinase 1 (Plk1) plays several roles in mitosis, and it has been suggested to have a role in tumorigenesis. We have previously reported that Plk1 depletion results in cell death in cancer cells, whereas normal cells survive similar depletion. However, Plk1 depletion together with p53 depletion induces cell death in normal cells as well. This communication presents evidence on the sequence of events that leads to cell death in cancer cells. DNA damage is detected at the first S phase following Plk1 depletion and is more severe in Plk1-depleted p53-null cancer cells. As a consequence of Plk1 depletion using lentivirus-based small interfering RNA techniques, prereplicative complex (pre-RC) formation is disrupted at the G1/S transition, and DNA synthesis is reduced during S phase of the first cycle after depletion. The levels of geminin, an inhibitor of DNA pre-RC, and Emi1, an inhibitor of anaphase-promoting complex/cyclosome, are elevated in Plk1-depleted cells. The rate of cell cycling is slower in Plk1-depleted cells than in control cells when synchronized by serum starvation. Plk1 depletion results in disrupted DNA pre-RC formation, reduced DNA synthesis, and DNA damage before cells display severe mitotic catastrophe or apoptosis. Our data suggest that Plk1 is required for cell cycle progression not only in mitosis but also for DNA synthesis, maintenance of DNA integrity, and prevention of cell death.</P>

Induction of G₁ Arrest by SB265610 Involves Cyclin D3 Downregulation and Suppression of CDK2 (Thr160) Phosphorylation

Goda, A. E.,Erikson, R. L.,Ahn, J.-S.,Kim, B.-Y. Potamitis Press 2015 Anticancer research Vol.35 No.6

<P>Background/Aim: The current study investigated the mechanisms underlying the antitumor activity of SB265610, a cysteine-amino acid-cysteine (CXC) chemokines receptor 2 (CXCR2) antagonist. Materials and Methods: Cell-cycle progression and regulatory molecules were assessed by flow cytometry, immunoblotting, real-time PCR and immunoprecipitation. Target validation was achieved via RNA interference. Results: G(1) arrest induced by SB265610 occurred at concentrations lacking CXCR2 selectivity, persisted upon interleukin 8 (IL8) challenge, and did not affect IL8 downstream target expression. Profiling of G(1) regulators revealed cyclin-dependent kinase 2 (CDK2) (Thr160) hypophosphorylation, cyclin D3 gene downregulation, and p21 post-translational induction. However, only cyclin D3 and CDK2 contributed towards G(1) arrest. Furthermore, SB265610 induced a sustained phosphorylation of the p38MAPK. Pharmacological interference with p38MAPK significantly abrogated SB265610-induced G(1) arrest and normalized the expression of cyclin D3, with restoration of its exclusive binding to CDK6, but with weak recovery of CDK2 (Thr160) hypo-phosphorylation. Conclusion: The present study described the mechanisms for the anti-proliferative activity of SB265610 which may be of value in IL8-rich tumor microenvironments.</P>

Preclinical evaluation of bortezomib/dipyridamole novel combination as a potential therapeutic modality for hematologic malignancies

Goda, A.E.,Erikson, R.L.,Sakai, T.,Ahn, J.S.,Kim, B.Y. Elsevier BV 2015 MOLECULAR ONCOLOGY Vol.9 No.1

Novel combinations aiming at maximizing the efficacy of bortezomib are highly valued in the clinic. Therefore the current study investigated the outcomes of combining bortezomib with dipyridamole, a well-known antiplatelet. The co-treatment exerted a synergistic lethality in a panel of human leukemia/lymphoma cell lines of different origin. Mechanistically, dipyridamole did not modulate the proteasome inhibitory activity of bortezomib. However, dipyridamole triggered an endoplasmic reticulum (ER) stress, and co-treatment with bortezomib resulted in higher levels of ER stress than either monotherapies. Relieving ER stress with the protein translation inhibitor, cycloheximide suppressed cell death. Moreover, the enhanced ER stress by the co-treatment was associated with an aggravation of reactive oxygen species (ROS) generation and glutathione (GSH) depletion. Replenishing GSH pools significantly scavenged ROS and rescued the cells. Importantly, the cytotoxicity of the co-treatment was executed mainly via the mitochondrial apoptotic pathway with an efficient suppression of the key anti-apoptotic regulators, Mcl-1, Bcl-xl, Bcl-2 and XIAP, driving the independence of the co-treatment-induced apoptosis of a single apoptotic trigger. Furthermore, the intrinsic potential of bortezomib to inhibit important pro-survival pathways was enhanced by dipyridamole in a GSH/ROS-dependent manner. Interestingly, dipyridamole abrogated JAK2 phosphorylation indirectly and selectively in cancer cells, and the co-treatment-induced cytotoxicity was preserved in a model of stromal-mediated chemoresistance. In nude mice, the antitumor activity of the co-treatment surpassed that of bortezomib monotherapy despite that synergy was lacking. In summary, findings of the present study provided a preclinical rationale which warrants further clinical evaluation of bortezomib/dipyridamole novel combination in hematologic malignancies.

Mechanistic mammalian target of rapamycin (MTOR) cell signaling: Effects of select nutrients and secreted phosphoprotein 1 on development of mammalian conceptuses

Bazer, Fuller W.,Song, Gwonhwa,Kim, Jinyoung,Erikson, David W.,Johnson, Greg A.,Burghardt, Robert C.,Gao, Haijun,Carey Satterfield, M.,Spencer, Thomas E.,Wu, Guoyao Elsevier 2012 Molecular and cellular endocrinology Vol.354 No.1

<P><B>Highlights</B></P><P>► Uterine epithelia secrete proteins and transport nutrients for conceptus development. ► Arginine and secreted phosphoprotein 1 (SPP1) activate MTOR cell signaling. ► Arginine metabolism to nitric oxide and polyamines stimulates conceptus growth. ► SPP1 induces focal adhesions between trophectoderm and uterine epithelia. ► Arginine and SPP1 stimulate conceptus development, implantation and pregnancy.</P> <P><B>Abstract</B></P><P>Morphological differentiation of uterine glands in mammals is a postnatal event vulnerable to adverse effects of endocrine disruptors. Exposure of ewe lambs to a progestin from birth to postnatal day 56 prevents development of uterine glands and, as adults, the ewes are unable to exhibit estrous cycles or maintain pregnancy. Uterine epithelia secrete proteins and transport nutrients into the uterine lumen necessary for conceptus development, pregnancy recognition signaling and implantation, including arginine and secreted phosphoprotein 1 (SPP1). Arginine can be metabolized to nitric oxide and to polyamines or act directly to activate MTOR cell signaling to stimulate proliferation, migration, and mRNA translation in trophectoderm cells. SPP1 binds αvβ3 and α5β1 integrins and induces focal adhesion assembly, adhesion and migration of conceptus trophectoderm cells during implantation. Thus, arginine and SPP1 mediate growth, migration, cytoskeletal remodeling and adhesion of trophectoderm essential for pregnancy recognition signaling and implantation.</P>

Embossed Structural Skin for Tall Buildings

Song, Jin Young,Lee, Donghun,Erikson, James,Hao, Jianming,Wu, Teng,Kim, Bonghwan Council on Tall Building and Urban Habitat Korea 2018 International journal of high-rise buildings Vol.7 No.1

This paper explores the function of a structural skin with an embossed surface applicable to use for tall building structures. The major diagrid system with a secondary embossed surface structure provides an enhanced perimeter structural system by increasing tube section areas and reduces aerodynamic loads by disorienting major organized structure of winds. A parametric study used to investigate an optimized configuration of the embossed structure revealed that the embossed structure has a structural advantage in stiffening the structure, reducing lateral drift to 90% compared to a non-embossed diagrid baseline model, and results of wind load analysis using computational fluid dynamics, demonstrated the proposed embossed system can reduce. The resulting undulating embossed skin geometry presents both opportunities for incorporating versatile interior environments as well as unique challenges for daylighting and thermal control of the envelope. Solar and thermal control requires multiple daylighting solutions to address each local façade surface condition in order to reduce energy loads and meet occupant comfort standards. These findings illustrate that although more complex in geometry, architects and engineers can produce tall buildings that have less impact on our environment by utilizing structural forms that reduce structural steel needed for stiffening, thus reducing embodied $CO^2$, while positively affecting indoor quality and energy performance, all possible while creating a unique urban iconography derived from the performance of building skin.

Essential role of Cenexin1, but not Odf2, in ciliogenesis

Chang, Jaerak,Seo, Sang,Lee, Kyung,Nagashima, Kunio,Bang, Jeong,Kim, Bo,Erikson, Raymond L.,Lee, Ki-Won,Lee, Hyong,Park, Jung-Eun,Lee, Kyung S. Taylor Francis 2013 Cell cycle Vol.12 No.4

Plk1-mediated stabilization of 53BP1 through USP7 regulates centrosome positioning to maintain bipolarity

Yim, H,Shin, S-B,Woo, S U,Lee, P C-W,Erikson, R L The Author(s) 2017 Oncogene Vol.36 No.7

<P>Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells. In addition, 53BP1 depletion reduces the levels of p53 and centromere protein F ( CENPF), interacting proteins of 53BP1. These phenotypes induced by 53BP1 depletion were rescued by expression of wild-type or phosphomimic mutant 53BP1 but not by expression of a dephosphomimic mutant. We propose that phosphorylation of 53BP1 at S380 accelerates complex formation with USP7 and CENPF to regulate their stability, thus having a crucial role in proper centrosome positioning, chromosomal alignment, and centrosome number.</P>

Crystal structure of constitutively monomeric E. coli Hsp33 mutant with chaperone activity

Chi, S.W.,Jeong, D.G.,Woo, J.R.,Lee, H.S.,Park, B.C.,Kim, B.Y.,Erikson, R.L.,Ryu, S.E.,Kim, S.J. North-Holland Pub ; Elsevier Science Ltd 2011 FEBS letters Vol.585 No.4

Heat shock protein 33 (Hsp33) from Escherichia coli is a redox-regulated molecular chaperone that protects cells from oxidative stress. To understand the molecular basis for the monomer-dimer switch in the functional regulation of E. coli Hsp33, we generated a constitutively monomeric Hsp33 by introducing the Q151E mutation in the dimeric interface and determined its crystal structure. The overall scaffold of the monomeric Hsp33<SUB>1-235</SUB> (Q151E) mutant is virtually the same as that of the dimeric form, except that there is no domain swapping. The measurement of chaperone activity to thermally denatured luciferase showed that the constitutively monomeric Hsp33 mutant still retains chaperone activity similar to that of wild-type Hsp33<SUB>1-235</SUB>, suggesting that a Hsp33 monomer is sufficient to interact with slowly unfolded substrate.

Metabolic Stress Controls mTORC1 Lysosomal Localization and Dimerization by Regulating the TTT-RUVBL½ Complex

Kim, S.,Hoffman, Gregory R.,Poulogiannis, G.,Buel, Gwen R.,Jang, Y.,Lee, K.,Kim, B.Y.,Erikson, Raymond L.,Cantley, Lewis C.,Choo, Andrew Y.,Blenis, J. Cell Press 2013 Molecular cell Vol.49 No.1

The metabolism of glucose and glutamine, primary carbon sources utilized by mitochondria to generate energy and macromolecules for cell growth, is directly regulated by mTORC1. We show that glucose and glutamine, by supplying carbons to the TCA cycle to produce ATP, positively feed back to mTORC1 through an AMPK-, TSC½-, and Rag-independent mechanism by regulating mTORC1 assembly and its lysosomal localization. We discovered that the ATP-dependent TTT-RUVBL½ complex was disassembled and repressed by energy depletion, resulting in its decreased interaction with mTOR. The TTT-RUVBL complex was necessary for the interaction between mTORC1 and Rag and formation of mTORC1 obligate dimers. In cancer tissues, TTT-RUVBL complex mRNAs were elevated and positively correlated with transcripts encoding proteins of anabolic metabolism and mitochondrial function-all mTORC1-regulated processes. Thus, the TTT-RUVBL½ complex responds to the cell's metabolic state, directly regulating the functional assembly of mTORC1 and indirectly controlling the nutrient signal from Rags to mTORC1.