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Kang, Hyunook,Bang, Injin,Jin, Kyeong Sik,Lee, Boyun,Lee, Junho,Shao, Xiangqiang,Heier, Jonathon A.,Kwiatkowski, Adam V.,Nelson, W. James,Hardin, Jeff,Weis, William I.,Choi, Hee-Jung American Society for Biochemistry and Molecular Bi 2017 The Journal of biological chemistry Vol.292 No.17
<P>Intercellular epithelial junctions formed by classical cadherins, beta-catenin, and the actin-binding protein alpha-catenin link the actin cytoskeletons of adjacent cells into a structural continuum. These assemblies transmit forces through the tissue and respond to intracellular and extracellular signals. However, the mechanisms of junctional assembly and regulation are poorly understood. Studies of cadherin-catenin assembly in a number of metazoans have revealed both similarities and unexpected differences in the biochemical properties of the cadherin center dot catenin complex that likely reflect the developmental and environmental requirements of different tissues and organisms. Here, we report the structural and biochemical characterization of HMP-1, the Caenorhabditis elegans alpha-catenin homolog, and compare it with mammalian alpha-catenin. HMP-1 shares overall similarity in structure and actin-binding properties, but displayed differences in conformational flexibility and allosteric regulation from mammalian alpha-catenin. HMP-1 bound filamentous actin with an affinity in the single micromolar range, even when complexed with the beta-catenin homolog HMP-2 or when present in a complex of HMP-2 and the cadherin homolog HMR-1, indicating that HMP-1 binding to F-actin is not allosterically regulated by the HMP-2.HMR-1 complex. The middle (i.e. M) domain of HMP-1 appeared to be less conformationally flexible than mammalian alpha-catenin, which may underlie the dampened effect of HMP-2 binding on HMP-1 actin-binding activity compared with that of the mammalian homolog. In conclusion, our data indicate that HMP-1 constitutively binds beta-catenin and F-actin, and although the overall structure and function of HMP-1 and related alpha-catenins are similar, the vertebrate proteins appear to be under more complex conformational regulation.</P>
Current Management Strategy of Nasopharyngeal Carcinoma
William I. Wei,Dora L. W. Kwong 대한이비인후과학회 2010 Clinical and Experimental Otorhinolaryngology Vol.3 No.1
Nasopharyngeal carcinoma is an unique head and neck cancer. It is common among the southern Chinese and is closely associated with the Epstein Barr virus (EBV). To diagnose the disease in its early stage is infrequent as the symptoms are usually trivial and patients only present in late stages. Testing the blood for elevated EBV DNA has now become a screening test for the high risk group of patients, aiming to diagnose the disease in its early stages. Imaging studies, positron emission tomography scans in addition to clinical examination provide information on the extent of the disease. The confirmation of the disease still depends on endoscopic examination and biopsy. Radiotherapy with or without chemotherapy has been the primary treatment modality. The application of intensity modulated radiotherapy and the use of concomitant chemoradiation have improved the control of nasopharyngeal carcinoma together with the reduction of long term side effects. The early detection of residual or recurrence tumor in the neck or at the primary site has allowed delivery of salvage treatment. The choice of the optimal surgical salvage, either for neck disease or primary tumor depends on the extent of the residual or recurrent disease. The outcome of these patients have improved with the application of the appropriate surgical salvage.
Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration
Zhang, Yongyou,Desai, Amar,Yang, Sung Yeun,Bae, Ki Beom,Antczak, Monika I.,Fink, Stephen P.,Tiwari, Shruti,Willis, Joseph E.,Williams, Noelle S.,Dawson, Dawn M.,Wald, David,Chen, Wei-Dong,Wang, Zhengh American Association for the Advancement of Scienc 2015 Science Vol.348 No.6240
<P><B>A shot in the arm for damaged tissue</B></P><P>Tissue damage can be caused by injury, disease, and even certain medical treatments. There is great interest in identifying drugs that accelerate tissue regeneration and recovery, especially drugs that might benefit multiple organ systems. Zhang <I>et al.</I> describe a compound with this desired activity, at least in mice (see the Perspective by FitzGerald). SW033291 promotes recovery of the hematopoietic system after bone marrow transplantation, prevents the development of ulcerative colitis in the intestine, and accelerates liver regeneration after hepatic surgery. It acts by inhibiting an enzyme that degrades prostaglandins, lipid signaling molecules that have been implicated in tissue stem cell maintenance.</P><P><I>Science</I>, this issue 10.1126/science.aaa2340; see also p. 1208</P><P>Agents that promote tissue regeneration could be beneficial in a variety of clinical settings, such as stimulating recovery of the hematopoietic system after bone marrow transplantation. Prostaglandin PGE2, a lipid signaling molecule that supports expansion of several types of tissue stem cells, is a candidate therapeutic target for promoting tissue regeneration in vivo. Here, we show that inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs in mice. In a chemical screen, we identify a small-molecule inhibitor of 15-PGDH (SW033291) that increases prostaglandin PGE2 levels in bone marrow and other tissues. SW033291 accelerates hematopoietic recovery in mice receiving a bone marrow transplant. The same compound also promotes tissue regeneration in mouse models of colon and liver injury. Tissues from 15-PGDH knockout mice demonstrate similar increased regenerative capacity. Thus, 15-PGDH inhibition may be a valuable therapeutic strategy for tissue regeneration in diverse clinical contexts.</P>
Hot Electron Field Emission <i>via</i> Individually Transistor-Ballasted Carbon Nanotube Arrays
Li, Chi,Zhang, Yan,Cole, Matthew T.,Shivareddy, Sai G.,Barnard, Jon S.,Lei, Wei,Wang, Baoping,Pribat, Didier,Amaratunga, Gehan A. J.,Milne, William I. American Chemical Society 2012 ACS NANO Vol.6 No.4
<P>We present electronically controlled field emission characteristics of arrays of individually ballasted carbon nanotubes synthesized by plasma-enhanced chemical vapor deposition on silicon-on-insulator substrates. By adjusting the source–drain potential we have demonstrated the ability to controllable limit the emission current density by more than 1 order of magnitude. Dynamic control over both the turn-on electric field and field enhancement factor have been noted. A hot electron model is presented. The ballasted nanotubes are populated with hot electrons due to the highly crystalline Si channel and the high local electric field at the nanotube base. This positively shifts the Fermi level and results in a broad energy distribution about this mean, compared to the narrow spread, lower energy thermalized electron population in standard metallic emitters. The proposed vertically aligned carbon nanotube field-emitting electron source offers a viable platform for X-ray emitters and displays applications that require accurate and highly stable control over the emission characteristics.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/ancac3/2012/ancac3.2012.6.issue-4/nn300111t/production/images/medium/nn-2012-00111t_0006.gif'></P>
Choi, H.J.,Loveless, T.,Lynch, A.M.,Bang, I.,Hardin, J.,Weis, William I. Cell Press 2015 DEVELOPMENTAL CELL Vol.33 No.1
<P>In metazoan adherens junctions, beta-catenin links the cytoplasmic tail of classical cadherins to the F-actin-binding protein a-catenin. Phosphorylation of a Ser/Thr-rich region in the cadherin tail dramatically enhances affinity for beta-catenin and promotes cell-cell adhesion in cell culture systems, but its importance has not been demonstrated in vivo. Here, we identify a critical phosphorylated serine in the C. elegans cadherin HMR-1 required for strong binding to the beta-catenin homolog HMP-2. Ablation of this phosphoserine interaction produces developmental defects that resemble full loss-of-function ( Hammerhead and Humpback) phenotypes. Most metazoans possess a single gene for beta-catenin, which is also a transcriptional coactivator in Wnt signaling. Nematodes and planaria, however, have a set of paralogous beta-catenins; for example, C. elegans HMP-2 functions only in cell-cell adhesion, whereas SYS-1 mediates transcriptional activation through interactions with POP-1/Tcf. Our structural data define critical sequence differences responsible for the unique ligand specificities of these two proteins.</P>
Shao, Xiangqiang,Kang, Hyunook,Loveless, Timothy,Lee, Gyu Rie,Seok, Chaok,Weis, William I.,Choi, Hee-Jung,Hardin, Jeff American Society for Biochemistry and Molecular Bi 2017 The Journal of biological chemistry Vol.292 No.40
<P>Stable tissue integrity during embryonic development relies on the function of the cadherin center dot catenin complex (CCC). The Caenorhabditis elegans CCC is a useful paradigm for analyzing in vivo requirements for specific interactions among the core components of the CCC, and it provides a unique opportunity to examine evolutionarily conserved mechanisms that govern the interaction between alpha- and beta-catenin. HMP-1, unlike its mammalian homolog alpha-catenin, is constitutively monomeric, and its binding affinity for HMP-2/beta-catenin is higher than that of alpha-catenin for beta-catenin. A crystal structure shows that the HMP-1 center dot HMP-2 complex forms a five-helical bundle structure distinct from the structure of the mammalian alpha-catenin beta-catenin complex. Deletion analysis based on the crystal structure shows that the first helix of HMP-1 is necessary for binding HMP-2 avidly in vitro and for efficient recruitment of HMP-1 to adherens junctions in embryos. HMP-2 Ser-47 and Tyr-69 flank its binding interface with HMP-1, and we show that phosphomimetic mutations at these two sites decrease binding affinity of HMP-1 to HMP-2 by 40-100-fold in vitro. In vivo experiments using HMP-2 S47E and Y69E mutants showed that they are unable to rescue hmp-2(zu364) mutants, suggesting that phosphorylation of HMP-2 on Ser-47 and Tyr-69 could be important for regulating CCC formation in C. elegans. Our data provide novel insights into how cadherin-dependent cell-cell adhesion is modulated in metazoans by conserved elements as well as features unique to specific organisms.</P>