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https://www.readbyqxmd.com/read/28098200/cullin-7-mediates-proteasomal-and-lysosomal-degradations-of-rat-eag1-potassium-channels
#1
Po-Hao Hsu, Yu-Ting Ma, Ya-Ching Fang, Jing-Jia Huang, Yu-Ling Gan, Pei-Tzu Chang, Guey-Mei Jow, Chih-Yung Tang, Chung-Jiuan Jeng
Mammalian Eag1 (Kv10.1) potassium (K(+)) channels are widely expressed in the brain. Several mutations in the gene encoding human Eag1 K(+) channel have been associated with congenital neurodevelopmental anomalies. Currently very little is known about the molecules mediating protein synthesis and degradation of Eag1 channels. Herein we aim to ascertain the protein degradation mechanism of rat Eag1 (rEag1). We identified cullin 7 (Cul7), a member of the cullin-based E3 ubiquitin ligase family, as a novel rEag1 binding partner...
January 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28096463/deneddylase1-counters-automodification-of-neddylating-enzymes-to-maintain-nedd8-homeostasis-in-arabidopsis
#2
Julia Mergner, Bernhard Kuster, Claus Schwechheimer
In eukaryotes, the conjugation of the ubiquitin-like protein NEDD8 onto protein targets is an important post-translational modification. The best understood neddylation targets are the cullins, scaffold subunits of E3 ubiquitin ligases, where neddylation as well as deneddylation, facilitated by the protease activity of the CSN (COP9 signalosome), are required to control ubiquitin ligase assembly, function and ultimately substrate degradation. Little is known about the role of other deneddylating enzymes besides CSN and the role of neddylation and deneddylation of their substrates...
January 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28089830/tumor-suppressor-spop-ubiquitinates-and-degrades-egln2-to-compromise-growth-of-prostate-cancer-cells
#3
Linli Zhang, Shan Peng, Xiangpeng Dai, Wenjian Gan, Xin Nie, Wenyi Wei, Guoqing Hu, Jianping Guo
EglN prolyl hydroxylases, a family of oxygen-sensing enzymes, hydroxylate distinct proteins to modulate diverse physiopathological signals. Aberrant regulations of EglNs result in multiple human diseases, including cancer. Different from EglN1 which function largely depends on the role of hypoxia-induce factor alpha (HIFα) in tumors, the functional significance and the upstream regulatory mechanisms of EglN2, especially in prostate cancer setting, remain largely unclear. Here, we demonstrated that dysregulation of EglN2 facilitated prostate cancer growth both in cells and in vivo...
January 13, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28087699/activation-of-c-abl-kinase-potentiates-the-anti-myeloma-drug-lenalidomide-by-promoting-dda1-recruitment-to-the-crl4-ubiquitin-ligase
#4
Shaobing Gao, Chenlu Geng, Tianyu Song, Xuanru Lin, Jiye Liu, Zhen Cai, Yong Cang
Cullin Ring Ligase 4 (CRL4), a complex of Cul4 and DDB1, regulates cell cycle, DNA damage repair, and chromatin replication by targeting a variety of substrates for ubiquitination. CRL4 is also hijacked by viral proteins or thalidomide-derived compounds to degrade host restriction factors. Here we report that the c-Abl non-receptor kinase phosphorylates DDB1 at residue Y316 to recruit a small regulatory protein DDA1, leading to increased substrate ubiquitination. Pharmacological inhibition or genetic ablation of the Abl-DDB1-DDA1 axis decreases the ubiquitination of CRL4 substrates, including IKZF1 and IKZF3 in lenalidomide-treated multiple myeloma cells...
January 13, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28071842/tip-enhanced-raman-spectroscopy-to-distinguish-toxic-oligomers-from-a%C3%AE-1-42-fibrils-at-the-nanometer-scale
#5
Sébastien Bonhommeau, David Talaga, Julien Hunel, Christophe Cullin, Sophie Lecomte
For the first time, natural Aβ1-42 fibrils (WT) implicated in Alzheimer's disease, as well as two synthetic mutants forming less toxic amyloid fibrils (L34T) and highly toxic oligomers (oG37C), are chemically characterized at the scale of a single structure using tip-enhanced Raman spectroscopy (TERS). While the proportion of TERS features associated with amino acid residues is similar for the three peptides, a careful examination of amide I and amide III bands allows us to clearly distinguish WT and L34T fibers organized in parallel β-sheets from the small and more toxic oG37C oligomers organized in anti-parallel β-sheets...
January 10, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28052114/crl4wdr1-controls-polo-like-kinase-protein-abundance-to-promote-bilobe-duplication-basal-body-segregation-and-flagellum-attachment-in-trypanosoma-brucei
#6
Huiqing Hu, Qing Zhou, Xianxian Han, Ziyin Li
The Polo-like kinase homolog in Trypanosoma brucei, TbPLK, plays essential roles in basal body segregation, flagellum attachment and cytokinesis. The level of TbPLK protein is tightly controlled, but the underlying mechanism remains elusive. Here, we report a Cullin-RING ubiquitin ligase composed of Cullin4, the DNA damage-binding protein 1 homolog TbDDB1 and a WD40-repeat protein WDR1 that controls TbPLK abundance in the basal body and the bilobe. WDR1, through its C-terminal domain, interacts with the PEST motif in TbPLK and, through its N-terminal WD40 motif, binds to TbDDB1...
January 2017: PLoS Pathogens
https://www.readbyqxmd.com/read/28035772/deregulated-neddylation-in-liver-fibrosis
#7
Imanol Zubiete-Franco, Pablo Fernández-Tussy, Lucía Barbier-Torres, Jorge Simon, David Fernández-Ramos, Fernando Lopitz-Otsoa, Virginia Gutiérrez-de Juan, Sergio López de Davalillo, Antonio Martín Duce, Paula Iruzubieta, Daniel Taibo, Javier Crespo, Juan Caballeria, Erica Villa, Igor Aurrekoetxea, Patricia Aspichueta, Marta Varela-Rey, Shelly C Lu, José M Mato, Naiara Beraza, Teresa C Delgado, María L Martínez-Chantar
: Hepatic fibrosis is a global health problem currently without effective therapeutic approaches. Even though the ubiquitin-like posttranslational modification of neddylation, that conjugates Nedd8 (neural precursor cell expressed developmentally downregulated) to specific targets, is aberrant in many pathologies, its relevance in liver fibrosis (LF) remained unexplored. Our results show deregulated neddylation in clinical fibrosis and both in mouse bileductligation- and CCl4 -induced fibrosis...
November 7, 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28032862/cullin-4-regulates-wingless-and-jnk-signaling-mediated-cell-death-in-the-drosophila-eye
#8
Meghana Tare, Ankita Sarkar, Shimpi Bedi, Madhuri Kango-Singh, Amit Singh
In all multicellular organisms, the fundamental processes of cell proliferation and cell death are crucial for growth regulation during organogenesis. Strict regulation of cell death is important to maintain tissue homeostasis by affecting processes like regulation of cell number, and elimination of unwanted/unfit cells. The developing Drosophila eye is a versatile model to study patterning and growth, where complex signaling pathways regulate growth and cell survival. However, the molecular mechanisms underlying regulation of these processes is not fully understood...
December 29, 2016: Cell Death & Disease
https://www.readbyqxmd.com/read/27987332/neddylated-cullin-3-is-required-for-vascular-endothelial-cadherin-mediated-endothelial-barrier-function
#9
Tomohisa Sakaue, Ayako Fujisaki, Hironao Nakayama, Masashi Maekawa, Hiromi Hiyoshi, Eiji Kubota, Takashi Joh, Hironori Izutani, Shigeki Higashiyama
Vascular endothelial-cadherin, a major endothelial adhesion molecule, regulates vascular permeability, and increased vascular permeability has been observed in several cancers. The aim of this study was to elucidate the role of the NEDD8-Cullin E3 ligase, in maintaining barrier permeability. To this end, we investigated the effects of the inhibition of Cullin E3 ligases, by using inhibitors and knockdown techniques in human umbilical vein endothelial cells. Further, we analyzed the mRNA and protein levels of the ligases by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively...
December 17, 2016: Cancer Science
https://www.readbyqxmd.com/read/27983981/cul4a-functions-as-an-oncogene-in-ovarian-cancer-and-is-directly-regulated-by-mir-494
#10
Xiaoni Han, Ziling Fang, Heng Wang, Rongfang Jiao, Jing Zhou, Nian Fang
Cullin 4A (CUL4A), as a well-defined oncogene, has been reported to be upregulated in ovarian cancer clinically. However, the biological functions of CUL4A and the molecular mechanism underlying its upregulation in ovarian cancer remains unknown throughly. Here, we show that expression of CUL4A is significantly higher in ovarian cancer tissues compared to corresponding non-cancerous tissues. Moreover, silencing of CUL4A by siRNA markedly inhibits cell proliferation, invasion and epithelial-mesenchymal transition (EMT)...
October 27, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27981705/azaindoles-as-zinc-binding-small-molecule-inhibitors-of-the-jamm-protease-csn5
#11
Eva Altmann, Paul Erbel, Martin Renatus, Michael Schaefer, Anita Schlierf, Adelaide Druet, Laurence Kieffer, Mickael Sorge, Keith Pfister, Ulrich Hassiepen, Matthew Jones, Simon Ruedisser, Daniela Ostermeier, Bruno Martoglio, Anne B Jefferson, Jean Quancard
CSN5 is the zinc metalloprotease subunit of the COP9 signalosome (CSN), which is an important regulator of cullin-RING E3 ubiquitin ligases (CRLs). CSN5 is responsible for the cleavage of NEDD8 from CRLs, and blocking deconjugation of NEDD8 traps the CRLs in a hyperactive state, thereby leading to auto-ubiquitination and ultimately degradation of the substrate recognition subunits. Herein, we describe the discovery of azaindoles as a new class of CSN5 inhibitors, which interact with the active-site zinc ion of CSN5 through an unprecedented binding mode...
December 16, 2016: Angewandte Chemie
https://www.readbyqxmd.com/read/27974468/dysregulation-of-cul4a-and-cul4b-ubiquitin-ligases-in-lung-cancer
#12
Lei Jia, Fan Yan, Wenfeng Cao, Zhengming Chen, Hong Zheng, Haixin Li, Yi Pan, Navneet Narula, Xiubao Ren, Hui Li, Pengbo Zhou
The Cullin-RING ubiquitin ligases 4 is implicated in controlling cell cycle, DNA damage repair and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human cancer patients. In our study, 352 lung cancer and 62 normal lung specimens of Asian origin were constructed into tissue microarrays (TMAs) of four distinct lung cancer subtypes...
December 14, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27956554/protein-neddylation-pathway-in-trypanosoma-brucei-functional-characterization-and-substrate-identification
#13
Shanhui Liao, Huiqing Hu, Tao Wang, Xiaoming Tu, Ziyin Li
Protein post-translational modifications, such as neddylation, play crucial roles in regulating protein function. Only a few neddylated substrates have been validated to date, and the role of neddylation remains poorly understood. Here, using Trypanosoma brucei as the model organism, we investigated the function and substrates of TbNedd8. TbNedd8 is distributed throughout the cytosol, but is enriched in the nucleus and the flagellum. Depletion of TbNedd8 by RNAi abolished global protein ubiquitination, caused DNA re-replication in post-mitotic cells, impaired spindle assembly, and compromised the flagellum attachment zone filament, leading to flagellum detachment...
December 12, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27955654/depletion-of-sag-rbx2-e3-ubiquitin-ligase-suppresses-prostate-tumorigenesis-via-inactivation-of-the-pi3k-akt-mtor-axis
#14
Mingjia Tan, Jie Xu, Javed Siddiqui, Felix Feng, Yi Sun
BACKGROUND: SAG (Sensitive to Apoptosis Gene), also known as RBX2, ROC2 or RNF7, is a RING component of CRL (Cullin-RING ligase), required for its activity. Our recent study showed that SAG/RBX2 co-operated with Kras to promote lung tumorigenesis, but antagonized Kras to inhibit skin tumorigenesis, suggesting a tissue/context dependent function of Sag. However, it is totally unknown whether and how Sag would play in prostate tumorigenesis, triggered by Pten loss. METHODS: Sag and Pten double conditional knockout mice were generated and prostate specific deletion of Sag and Pten was achieved by PB4-Cre, and their effect on prostate tumorigenesis was evaluated by H&E staining...
December 12, 2016: Molecular Cancer
https://www.readbyqxmd.com/read/27941885/dbc2-rhobtb2-functions-as-a-tumor-suppressor-protein-via-musashi-2-ubiquitination-in-breast-cancer
#15
Y M Choi, K B Kim, J H Lee, Y K Chun, I S An, S An, S Bae
The gene encoding 'deleted in breast cancer 2' (DBC2), also referred to as RHOBTB2 (Rho-related BTB domain-containing protein 2), is classified as a tumor suppressor gene. DBC2 is a substrate-specific adaptor protein for a novel class of Cullin-3 (CUL3)-based E3 ubiquitin ligases; however, it is unclear if the substrate adaptor function of DBC2 is required for its tumor suppressor activity. Furthermore, the key substrates of DBC2-mediated ubiquitination have yet to be identified. In the present study, we established a genome-wide human cDNA library-based in vitro ubiquitination target screening assay and identified Musashi-2 (MSI2) as a novel ubiquitination target protein of DBC2...
December 12, 2016: Oncogene
https://www.readbyqxmd.com/read/27940122/pediatric-community-mental-health
#16
Lisa M Cullins, Mary Gabriel, Martine Solages, David Call, Shalice McKnight, Milangel Concepcion, Jang Cho
The emotional health and wellbeing of children and adolescents and their families is of utmost importance. Pediatricians are at the front line in identifying mental illness in children and adolescents and either linking them to resources in the community or providing treatment options themselves. Collaboration and integrative health care models is the cornerstone of effective strategies to provide access and quality mental health care to children and families in communities across the country.
November 2016: Current Problems in Pediatric and Adolescent Health Care
https://www.readbyqxmd.com/read/27930311/spop-promotes-skeletal-development-and-homeostasis-by-positively-regulating-ihh-signaling
#17
Hongchen Cai, Aimin Liu
Indian Hedgehog (Ihh) regulates chondrocyte and osteoblast differentiation through the Glioma-associated oncogene homolog (Gli) transcription factors. Previous in vitro studies suggested that Speckle-type POZ protein (Spop), part of the Cullin-3 (Cul3) ubiquitin ligase complex, targets Gli2 and Gli3 for degradation and negatively regulates Hedgehog (Hh) signaling. In this study, we found defects in chondrocyte and osteoblast differentiation in Spop-null mutant mice. Strikingly, both the full-length and repressor forms of Gli3, but not Gli2, were up-regulated in Spop mutants, and Ihh target genes Patched 1 (Ptch1) and parathyroid hormone-like peptide (Pthlh) were down-regulated, indicating compromised Hh signaling...
December 20, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27919712/extracts-from-two-ubiquitous-mediterranean-plants-ameliorate-cellular-and-animal-models-of-neurodegenerative-proteinopathies
#18
Michelle Briffa, Stephanie Ghio, Johanna Neuner, Alison J Gauci, Rebecca Cacciottolo, Christelle Marchal, Mario Caruana, Christophe Cullin, Neville Vassallo, Ruben J Cauchi
A signature feature of age-related neurodegenerative proteinopathies is the misfolding and aggregation of proteins, typically amyloid-β (Aβ) in Alzheimer's disease (AD) and α-synuclein (α-syn) in Parkinson's disease (PD), into soluble oligomeric structures that are highly neurotoxic. Cellular and animal models that faithfully replicate the hallmark features of these disorders are being increasing exploited to identify disease-modifying compounds. Natural compounds have been identified as a useful source of bioactive molecules with promising neuroprotective capabilities...
December 2, 2016: Neuroscience Letters
https://www.readbyqxmd.com/read/27910872/sag-rbx2-e3-ligase-complexes-with-ubch10-and-ube2s-e2s-to-ubiquitylate-%C3%AE-trcp1-via-k11-linkage-for-degradation
#19
Peng Kuang, Mingjia Tan, Weihua Zhou, Qiang Zhang, Yi Sun
SAG/RBX2 and RBX1 are two family members of RING components of Cullin-RING ligases (CRLs), required for their enzymatic activity. Previous studies showed that SAG prefers to bind with CUL5, as well as CUL1, whereas RBX1 binds exclusively to CULs1-4. Detailed biochemical difference between SAG and RBX1, and whether SAG mediates cross-talk between CRL5 and CRL1 are previously unknown. Here we report that the levels of SAG and β-TrCP1 are inversely correlated, and SAG-CUL5-βTrCP1 forms a complex under physiological condition...
December 2, 2016: Scientific Reports
https://www.readbyqxmd.com/read/27906189/distinct-outcomes-of-crl-nedd8-pathway-inhibition-reveal-cancer-cell-plasticity
#20
Anastasia V Rulina, Frédérique Mittler, Patricia Obeid, Sophie Gerbaud, Laurent Guyon, Eric Sulpice, Frédérique Kermarrec, Nicole Assard, Monika E Dolega, Xavier Gidrol, Maxim Y Balakirev
Inhibition of protein degradation by blocking Cullin-RING E3 ligases (CRLs) is a new approach in cancer therapy though of unknown risk because CRL inhibition may stabilize both oncoproteins and tumor suppressors. Probing CRLs in prostate cancer cells revealed a remarkable plasticity of cells with TMPRSS2-ERG translocation. CRL suppression by chemical inhibition or knockdown of RING component RBX1 led to reversible G0/G1 cell cycle arrest that prevented cell apoptosis. Conversely, complete blocking of CRLs at a higher inhibitor dose-induced cytotoxicity that was amplified by knockdown of CRL regulator Cand1...
December 1, 2016: Cell Death & Disease
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