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ERCC1‐XPF endonuclease-positioned to cut
Schä,rer, Orlando D EMBO 2017 The EMBO journal Vol.36 No.14
<P>To counteract damage to our genomes, numerous endo-and exonucleases incise the DNA backbone to remove damaged and aberrant DNA structures. It is imperative that such incisions be very tightly controlled, as unwanted DNA breaks are a key source of genome instability. Two new papers in The EMBO Journal shed light on how the activity of one such nuclease-ERCC1-XPF, an enzyme involved in various DNA repair pathways-is regulated to perform incision in the vicinity of DNA interstrand crosslinks.</P>
Park, Min Hee,Jin, Hee Kyung,Min, Woo‐,Kie,Lee, Won Woo,Lee, Jeong Eun,Akiyama, Haruhiko,Herzog, Herbert,Enikolopov, Grigori N,Schuchman, Edward H,Bae, Jae‐,sung EMBO 2015 The EMBO journal Vol.34 No.12
<P>Many reports have revealed the importance of the sympathetic nervous system (SNS) in the control of the bone marrow environment. However, the specific role of neuropeptide Y (NPY) in this process has not been systematically studied. Here we show that NPY-deficient mice have significantly reduced hematopoietic stem cell (HSC) numbers and impaired regeneration in bone marrow due to apoptotic destruction of SNS fibers and/or endothelial cells. Furthermore, pharmacological elevation of NPY prevented bone marrow impairments in a mouse model of chemotherapy-induced SNS injury, while NPY injection into conditional knockout mice lacking the Y1 receptor in macrophages did not relieve bone marrow dysfunction. These results indicate that NPY promotes neuroprotection and restores bone marrow dysfunction from chemotherapy-induced SNS injury through the Y1 receptor in macrophages. They also reveal a new role of NPY as a regulator of the bone marrow microenvironment and highlight the potential therapeutic value of this neuropeptide.</P>
Filamin is essential for shedding of the transmembrane serine protease, epithin
Kim, Chungho,Cho, Yongcheol,Kang, Chan‐,Hee,Kim, Moon Gyo,Lee, HyoSeon,Cho, Eun‐,Gyung,Park, Dongeun EMBO 2005 EMBO reports Vol.6 No.11
<P>Epithin is a type II transmembrane serine protease that exists in a soluble and membrane-bound form. Shedding is thought to be important in regulating its action, but little is known regarding the intracellular events that trigger such shedding. Here, we show that phorbol myristate acetate (PMA) causes the release of epithin. It also causes accumulation of the protein at the site of cell-cell contacts, and this accumulation is dependent on the formation of cortical actin. In addition, we have identified the actin-binding protein, filamin, as the linker between epithin and the actin cytoskeleton. The interaction of epithin and filamin was enhanced by PMA, and epithin was not released from filamin-deficient M2 cells. We also show that the release of epithin does not require its own activity and is blocked by a metalloprotease inhibitor, GM6001. These results show that filamin has an essential role in shedding by linking epithin to the as yet unidentified metalloprotease-shedding enzyme(s).</P>
Lee, Yun‐,Suk,Jang, Moon‐,Sun,Lee, Jong‐,Soo,Choi, Eui‐,Ju,Kim, Eunhee EMBO 2005 EMBO reports Vol.6 No.10
<P>This study examined whether small ubiquitin-related modifier-1 (SUMO-1) regulates apoptosis signal-regulating kinase 1 (ASK 1). ASK 1 interacted with SUMO-1 in vitro as well as in BOSC 23 cells. Endogenous ASK 1-SUMO-1 interaction was disrupted following H(2)O(2) signal. SUMO-1 overexpression suppressed the self-oligomerization, kinase activity and apoptotic potential of ASK 1, whereas SUMO-1 depletion potentiated such activities. SUMO-1(Delta C 6), a sumoylation-incompetent mutant lacking carboxy-terminal six amino acids, suppressed AS 1 activation, implying that the suppressive effect of SUMO-1 on ASK 1 is independent of sumoylation. ASK 1(3M), an ASK 1 mutant in which all three lysines in the psiKXE motif were substituted with alanines, still retained the kinase activity and activated the Jun amino-terminal kinase pathway. However, SUMO-1 failed to interact with ASK 1(3M) and to suppress ASK 1(3M) activation, indicating that the three lysines are important for regulation by SUMO-1. This study shows that SUMO-1 exerts a negative regulatory effect on ASK 1 activation through physical interaction and not through covalent modification.</P>
Strength of TRAF6 signalling determines osteoclastogenesis
Kadono, Yuho,Okada, Fumihiko,Perchonock, Claire,Jang, Hyun Duk,Lee, Soo Young,Kim, Nacksung,Choi, Yongwon EMBO 2005 EMBO reports Vol.6 No.2
<P>TRANCE/TRAF6 signalling governs osteoclastogenesis in vivo. Only the TRANCE receptor (TRANCE-R) has been shown to induce osteoclastogenesis, even though other immune receptors, including CD40 and IL-1R/Toll-like receptor, use TRAF6 to activate overlapping signalling cascades. These observations led us to question whether qualitative or quantitative differences exist between the TRAF6-mediated signals induced by TRANCE and by other ligand-receptor pairs. Here we show that stimulation by overexpressed wild-type CD40 can induce osteoclastogenesis. Stimulation through modified CD40 containing increased numbers of TRAF6-binding sites in the cytoplasmic tails showed a dose-dependent increase in the activation of p38 kinase and more pronounced osteoclastogenesis. Moreover, precursors overexpressing TRAF6 differentiate into osteoclasts in the absence of additional signals from TRANCE. Our results suggest that differences in the osteoclastogenesis-inducing capacity of TRANCE-R versus other TRAF6-associated receptors may in part stem from a quantitative difference in the TRAF6-mediated signals.</P>
Choi, Hee‐,Joo,Park, Ji‐,Hye,Park, Mikyung,Won, Hee‐,Young,Joo, Hyeong‐,seok,Lee, Chang Hoon,Lee, Jeong‐,Yeon,Kong, Gu EMBO 2015 EMBO reports Vol.16 No.10
<P>The histone H3K27 demethylase, UTX, is a known component of the H3K4 methyltransferase MLL complex, but its functional association with H3K4 methylation in human cancers remains largely unknown. Here we demonstrate that UTX loss induces epithelial-mesenchymal transition (EMT)-mediated breast cancer stem cell (CSC) properties by increasing the expression of the SNAIL, ZEB1 and ZEB2 EMT transcription factors (EMT-TFs) and of the transcriptional repressor CDH1. UTX facilitates the epigenetic silencing of EMT-TFs by inducing competition between MLL4 and the H3K4 demethylase LSD1. EMT-TF promoters are occupied by c-Myc and MLL4, and UTX recognizes these proteins, interrupting their transcriptional activation function. UTX decreases H3K4me2 and H3 acetylation at these promoters by forming a transcriptional repressive complex with LSD1, HDAC1 and DNMT1. Taken together, our findings indicate that UTX is a prominent tumour suppressor that functions as a negative regulator of EMT-induced CSC-like properties by epigenetically repressing EMT-TFs.</P>
Oncoprotein CIP 2A promotes the disassembly of primary cilia and inhibits glycolytic metabolism
Jeong, Ae Lee,Ka, Hye In,Han, Sora,Lee, Sunyi,Lee, Eun‐,Woo,Soh, Su Jung,Joo, Hyun Jeong,Sumiyasuren, Buyanravjkh,Park, Ji Young,Lim, Jong‐,Seok,Park, Jong Hoon,Lee, Myung Sok,Yang, Young EMBO 2018 EMBO reports Vol.19 No.5
Clusterin/ApoJ enhances central leptin signaling through Lrp2‐mediated endocytosis
Byun, Kyunghee,Gil, So Young,Namkoong, Churl,Youn, Byung‐,Soo,Huang, Hu,Shin, Mi‐,Seon,Kang, Gil Myoung,Kim, Hyun‐,Kyong,Lee, Bonghee,Kim, Young‐,Bum,Kim, Min‐,Seon EMBO 2014 EMBO reports Vol.15 No.7
<P>Hypothalamic leptin signaling plays a central role in maintaining body weight homeostasis. Here, we show that clusterin/ApoJ, recently identified as an anorexigenic neuropeptide, is an important regulator in the hypothalamic leptin signaling pathway. Coadministration of clusterin potentiates the anorexigenic effect of leptin and boosts leptin-induced hypothalamic Stat3 activation. In cultured neurons, clusterin enhances receptor binding and subsequent endocytosis of leptin. These effects are mainly mediated through the LDL receptor-related protein-2 (Lrp2). Notably, inhibition of hypothalamic clusterin, Lrp2 or endocytosis abrogates anorexia and hypothalamic Stat3 activation caused by leptin. These findings propose a novel regulatory mechanism in central leptin signaling pathways.</P>