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Endothelial Deletion of Phospholipase D2 Reduces Hypoxic Response and Pathological Angiogenesis
Ghim, Jaewang,Moon, Jin-Sook,Lee, Chang Sup,Lee, Junyeop,Song, Parkyong,Lee, Areum,Jang, Jin-Hyeok,Kim, Dayea,Yoon, Jong Hyuk,Koh, Young Jun,Chelakkot, Chaithanya,Kang, Byung Jun,Kim, Jung-Min,Kim, Ky American Heart Association, Inc. 2014 Arteriosclerosis, thrombosis, and vascular biology Vol.34 No.8
<P><B>Objective—</B></P><P>Aberrant regulation of the proliferation, survival, and migration of endothelial cells (ECs) is closely related to the abnormal angiogenesis that occurs in hypoxia-induced pathological situations, such as cancer and vascular retinopathy. Hypoxic conditions and the subsequent upregulation of hypoxia-inducible factor-1α and target genes are important for the angiogenic functions of ECs. Phospholipase D2 (PLD2) is a crucial signaling mediator that stimulates the production of the second messenger phosphatidic acid. PLD2 is involved in various cellular functions; however, its specific roles in ECs under hypoxia and in vivo angiogenesis remain unclear. In the present study, we investigated the potential roles of PLD2 in ECs under hypoxia and in hypoxia-induced pathological angiogenesis in vivo.</P><P><B>Approach and Results—</B></P><P><I>Pld2</I> knockout ECs exhibited decreased hypoxia-induced cellular responses in survival, migration, and thus vessel sprouting. Analysis of hypoxia-induced gene expression revealed that PLD2 deficiency disrupted the upregulation of hypoxia-inducible factor-1α target genes, including <I>VEGF</I>, <I>PFKFB3</I>, <I>HMOX-1</I>, and <I>NTRK2</I>. Consistent with this, PLD2 contributed to hypoxia-induced hypoxia-inducible factor-1α expression at the translational level. The roles of PLD2 in hypoxia-induced in vivo pathological angiogenesis were assessed using oxygen-induced retinopathy and tumor implantation models in endothelial-specific <I>Pld2</I> knockout mice. <I>Pld2</I> endothelial-specific knockout retinae showed decreased neovascular tuft formation, despite a larger avascular region. Tumor growth and tumor blood vessel formation were also reduced in <I>Pld2</I> endothelial-specific knockout mice.</P><P><B>Conclusions—</B></P><P>Our findings demonstrate a novel role for endothelial PLD2 in the survival and migration of ECs under hypoxia via the expression of hypoxia-inducible factor-1α and in pathological retinal angiogenesis and tumor angiogenesis in vivo.</P>
PML-IV functions as a negative regulator of telomerase by interacting with TERT.
Oh, Wonkyung,Ghim, Jaewang,Lee, Eun-Woo,Yang, Mi-Ran,Kim, Eui Tae,Ahn, Jin-Hyun,Song, Jaewhan Cambridge University Press 2009 Journal of cell science Vol.122 No.15
<P>Maintaining proper telomere length requires the presence of the telomerase enzyme. Here we show that telomerase reverse transcriptase (TERT), a catalytic component of telomerase, is recruited to promyelocytic leukemia (PML) nuclear bodies through its interaction with PML-IV. Treatment of interferon-alpha (IFNalpha) in H1299 cells resulted in the increase of PML proteins with a concurrent decrease of telomerase activity, as previously reported. PML depletion, however, stimulated telomerase activity that had been inhibited by IFNalpha with no changes in TERT mRNA levels. Upon treatment with IFNalpha, exogenous TERT localized to PML nuclear bodies and binding between TERT and PML increased. Immunoprecipitation and immunofluorescence analyses showed that TERT specifically bound to PML-IV. Residues 553-633 of the C-terminal region of PML-IV were required for its interaction with the TERT region spanning residues 1-350 and 595-946. The expression of PML-IV and its deletion mutant, 553-633, suppressed intrinsic telomerase activity in H1299. TERT-mediated immunoprecipitation of PML or the 553-633 fragment demonstrated that these interactions inhibited telomerase activity. H1299 cell lines stably expressing PML-IV displayed decreased telomerase activity with no change of TERT mRNA levels. Accordingly, telomere length of PML-IV stable cell lines was shortened. These results indicate that PML-IV is a negative regulator of telomerase in the post-translational state.</P>
BMB Reports : Loss of phospholipase D2 impairs VEGF-induced angiogenesis
( Chang Sup Lee ),( Jaewang Ghim ),( Parkyong Song ),( Pann Ghill Suh ),( Sung Ho Ryu ) 생화학분자생물학회(구 한국생화학분자생물학회) 2016 BMB Reports Vol.49 No.3
Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis and critical for normal embryonic development and repair of pathophysiological conditions in adults. Although phospholipase D (PLD) activity has been implicated in angiogenic processes, its role in VEGF signaling during angiogenesis in mammals is unclear. Here, we found that silencing of PLD2 by siRNA blocked VEGF-mediated signaling in immortalized human umbilical vein endothelial cells (iHUVECs). Also, VEGF-induced endothelial cell survival, proliferation, migration, and tube formation were inhibited by PLD2 silencing. Furthermore, while Pld2-knockout mice exhibited normal development, loss of PLD2 inhibited VEGF-mediated ex vivo angiogenesis. These findings suggest that PLD2 functions as a key mediator in the VEGF-mediated angiogenic functions of endothelial cells. [BMB Reports 2016; 49(3): 191-196]
Emodin Regulates Glucose Utilization by Activating AMP-activated Protein Kinase
Song, Parkyong,Kim, Jong Hyun,Ghim, Jaewang,Yoon, Jong Hyuk,Lee, Areum,Kwon, Yonghoon,Hyun, Hyunjung,Moon, Hyo-Youl,Choi, Hueng-Sik,Berggren, Per-Olof,Suh, Pann-Ghill,Ryu, Sung Ho American Society for Biochemistry and Molecular Bi 2013 The Journal of biological chemistry Vol.288 No.8
CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice.
Kim, Dayea,Kim, Jaeyoon,Yoon, Jong Hyuk,Ghim, Jaewang,Yea, Kyungmoo,Song, Parkyong,Park, Soyeon,Lee, Areum,Hong, Chun-Pyo,Jang, Min Seong,Kwon, Yonghoon,Park, Sehoon,Jang, Myoung Ho,Berggren, Per-Olof Springer Verlag 2014 Diabetologia Vol.57 No.7
<P>Obesity-induced inflammation is initiated by the recruitment of macrophages into adipose tissue. The recruited macrophages, called adipose tissue macrophages, secrete several proinflammatory cytokines that cause low-grade systemic inflammation and insulin resistance. The aim of this study was to find macrophage-recruiting factors that are thought to provide a crucial connection between obesity and insulin resistance.</P>
Lee, Sung Kyun,Kim, Sang Doo,Kook, Minsoo,Lee, Ha Young,Ghim, Jaewang,Choi, Youngwoo,Zabel, Brian A.,Ryu, Sung Ho,Bae, Yoe-Sik The Rockefeller University Press 2015 The Journal of experimental medicine Vol.212 No.9
<P>Lee et al. find that phospholipase D2 deficiency increases survival and decreases organ damage during experimental sepsis in mice which could be reversed with a CXCR2 antagonist. Thus, targeting PLD2 may offer therapeutics for septic patients.</P><P>We determined the function of phospholipase D2 (PLD2) in host defense in highly lethal mouse models of sepsis using PLD2<SUP>−/−</SUP> mice and a PLD2-specific inhibitor. PLD2 deficiency not only increases survival but also decreases vital organ damage during experimental sepsis. Production of several inflammatory cytokines (TNF, IL-1β, IL-17, and IL-23) and the chemokine CXCL1, as well as cellular apoptosis in immune tissues, kidney, and liver, are markedly decreased in PLD2<SUP>−/−</SUP> mice. Bactericidal activity is significantly increased in PLD2<SUP>−/−</SUP> mice, which is mediated by increased neutrophil extracellular trap formation and citrullination of histone 3 through peptidylarginine deiminase activation. Recruitment of neutrophils to the lung is markedly increased in PLD2<SUP>−/−</SUP> mice. Furthermore, LPS-induced induction of G protein–coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly attenuated in PLD2<SUP>−/−</SUP> mice. A CXCR2-selective antagonist abolishes the protection conferred by PLD2 deficiency during experimental sepsis, suggesting that enhanced CXCR2 expression, likely driven by GRK2 down-regulation in neutrophils, promotes survival in PLD2<SUP>−/−</SUP> mice. Furthermore, adoptively transferred PLD2<SUP>−/−</SUP> neutrophils significantly protect WT recipients against sepsis-induced death compared with transferred WT neutrophils. We suggest that PLD2 in neutrophils is essential for the pathogenesis of experimental sepsis and that pharmaceutical agents that target PLD2 may prove beneficial for septic patients.</P>
Differential regulation of p53 and p21 by MKRN1 E3 ligase controls cell cycle arrest and apoptosis.
Lee, Eun-Woo,Lee, Min-Sik,Camus, Suzanne,Ghim, Jaewang,Yang, Mi-Ran,Oh, Wonkyung,Ha, Nam-Chul,Lane, David P,Song, Jaewhan Published for the European Molecular Biology Organ 2009 The EMBO journal Vol.28 No.14
<P>Makorin Ring Finger Protein 1 (MKRN1) is a transcriptional co-regulator and an E3 ligase. Here, we show that MKRN1 simultaneously functions as a differentially negative regulator of p53 and p21. In normal conditions, MKRN1 could destabilize both p53 and p21 through ubiquitination and proteasome-dependent degradation. As a result, depletion of MKRN1 induced growth arrest through activation of p53 and p21. Interestingly, MKRN1 used earlier unknown sites, K291 and K292, for p53 ubiquitination and subsequent degradation. Under severe stress conditions, however, MKRN1 primarily induced the efficient degradation of p21. This regulatory process contributed to the acceleration of DNA damage-induced apoptosis by eliminating p21. MKRN1 depletion diminished adriamycin or ultraviolet-induced cell death, whereas ectopic expression of MKRN1 facilitated apoptosis. Furthermore, MKRN1 stable cell lines that constantly produced low levels of p53 and p21 exhibited stabilization of p53, but not p21, with increased cell death on DNA damage. Our results indicate that MKRN1 exhibits dual functions of keeping cells alive by suppressing p53 under normal conditions and stimulating cell death by repressing p21 under stress conditions.</P>
Koh, Ara,Lee, Mi Nam,Yang, Yong Ryoul,Jeong, Heeyoon,Ghim, Jaewang,Noh, Jeongeun,Kim, Jaeyoon,Ryu, Dongryeol,Park, Sehoon,Song, Parkyong,Koo, Seung-Hoi,Leslie, Nick R.,Berggren, Per-Olof,Choi, Jang Hy American Society for Microbiology 2013 Molecular and cellular biology Vol.33 No.8
<P>Muscle atrophy occurs under various catabolic conditions, including insulin deficiency, insulin resistance, or increased levels of glucocorticoids. This results from reduced levels of insulin receptor substrate 1 (IRS-1), leading to decreased phosphatidylinositol 3-kinase activity and thereby activation of FoxO transcription factors. However, the precise mechanism of reduced IRS-1 under a catabolic condition is unknown. Here, we report that C1-Ten is a novel protein tyrosine phosphatase (PTPase) of IRS-1 that acts as a mediator to reduce IRS-1 under a catabolic condition, resulting in muscle atrophy. C1-Ten preferentially dephosphorylated Y612 of IRS-1, which accelerated IRS-1 degradation. These findings suggest a novel type of IRS-1 degradation mechanism which is dependent on C1-Ten and extends our understanding of the molecular mechanism of muscle atrophy under catabolic conditions. C1-Ten expression is increased by catabolic glucocorticoid and decreased by anabolic insulin. Reflecting these hormonal regulations, the muscle C1-Ten is upregulated in atrophy but downregulated in hypertrophy. This reveals a previously unidentified role of C1-Ten as a relevant PTPase contributing to skeletal muscle atrophy.</P>
Phospholipase signalling networks in cancer
Park, Jong Bae,Lee, Chang Sup,Jang, Jin-Hyeok,Ghim, Jaewang,Kim, Youn-Jae,You, Sungyoung,Hwang, Daehee,Suh, Pann-Ghill,Ryu, Sung Ho Nature Publishing Group, a division of Macmillan P 2012 Nature reviews. Cancer Vol.12 No.11
Phospholipases (PLC, PLD and PLA) are essential mediators of intracellular and intercellular signalling. They can function as phospholipid-hydrolysing enzymes that can generate many bioactive lipid mediators, such as diacylglycerol, phosphatidic acid, lysophosphatidic acid and arachidonic acid. Lipid mediators generated by phospholipases regulate multiple cellular processes that can promote tumorigenesis, including proliferation, migration, invasion and angiogenesis. Although many individual phospholipases have been extensively studied, how phospholipases regulate diverse cancer-associated cellular processes and the interplay between different phospholipases have yet to be fully elucidated. A thorough understanding of the cancer-associated signalling networks of phospholipases is necessary to determine whether these enzymes can be targeted therapeutically.