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https://www.readbyqxmd.com/read/28447739/neural-precursor-cell-expressed-developmentally-downregulated-8%C3%A2-activating-enzyme-inhibitor-mln4924-sensitizes-colorectal-cancer-cells-to-oxaliplatin-by-inducing-dna-damage-g2-cell-cycle-arrest-and-apoptosis
#1
Wanwei Zheng, Zhongguang Luo, Jun Zhang, Pei Min, Wenshuai Li, Diannan Xu, Ziqiang Zhang, Panpan Xiong, Hong Liang, Jie Liu
Oxaliplatin-based chemotherapy is a primary treatment for patients with metastatic colorectal cancer (CRC); however, its efficacy is limited. Therefore, novel therapeutic agents are urgently required. MLN4924 is a first‑in‑class inhibitor of neural precursor cell expressed, developmentally downregulated 8 (NEDD8)‑activating enzyme E1, and has entered various phase‑I/II clinical trials for cancer therapy due to its significant anticancer efficacy. The aim of the present study was to examine the synergistic effect and underlying mechanisms of MLN4924 and oxaliplatin combined treatment for CRC...
March 9, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28446751/crl4b-dcaf11-e3-ligase-targets-p21-for-degradation-to-control-cell-cycle-progression-in-human-osteosarcoma-cells
#2
Zhi Chen, Kun Wang, Canglong Hou, Kaibiao Jiang, Bin Chen, Jianwei Chen, Lifeng Lao, Lie Qian, Guibin Zhong, Zude Liu, Caiguo Zhang, Hongxing Shen
Cell cycle progression in mammals is strictly controlled by a number of cyclin-dependent kinases (CDKs) and CDK inhibitors (CKIs), the expression of which is often dysregulated in cancer cells. Our previous work revealed that Cullin 4B (CUL4B), a critical component of the Cullin4B-RING E3 ligase complex (CRL4B), is overexpressed in human osteosarcoma cells through an unknown mechanism. Here, we demonstrated that CUL4B forms an E3 ligase with RBX1 (RING-box 1), DDB1 (DNA damage binding protein 1), and DCAF11 (DDB1 and CUL4 associated factor 11) in human osteosarcoma cells...
April 26, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28442889/cul4a-promotes-cell-invasion-in-gastric-cancer-by-activating-the-nf-%C3%AE%C2%BAb-signaling-pathway
#3
Yu Gong, Xiao-Jun Xiang, Miao Feng, Jun Chen, Zi-Ling Fang, Jian-Ping Xiong
Cullin 4A (CUL4A) overexpression has been reported to be involved in the carcinogenesis and progression of many malignant tumors. However, the role of CUL4A in the progression of gastric cancer (GC) remains unclear. In this study, we explored whether and how CUL4A regulates proinflammatory signaling to promote GC cell invasion. Our results showed that knockdown of CUL4A inhibited GC cell migration and invasion induced by lipopolysaccharide (LPS) stimulation. We also found that both CUL4A and nuclear factor-kappa B (NF-κB) protein expressions were enhanced by LPS stimulation in HGC27 GC cell lines...
2017: Biologics: Targets & Therapy
https://www.readbyqxmd.com/read/28437394/selective-degradation-of-splicing-factor-caper%C3%AE-by-anticancer-sulfonamides
#4
Taisuke Uehara, Yukinori Minoshima, Koji Sagane, Naoko Hata Sugi, Kaoru Ogawa Mitsuhashi, Noboru Yamamoto, Hiroshi Kamiyama, Kentaro Takahashi, Yoshihiko Kotake, Mai Uesugi, Akira Yokoi, Atsushi Inoue, Taku Yoshida, Miyuki Mabuchi, Akito Tanaka, Takashi Owa
Target-protein degradation is an emerging field in drug discovery and development. In particular, the substrate-receptor proteins of the cullin-ubiquitin ligase system play a key role in selective protein degradation, which is an essential component of the anti-myeloma activity of immunomodulatory drugs (IMiDs), such as lenalidomide. Here, we demonstrate that a series of anticancer sulfonamides NSC 719239 (E7820), indisulam, and NSC 339004 (chloroquinoxaline sulfonamide, CQS) induce proteasomal degradation of the U2AF-related splicing factor coactivator of activating protein-1 and estrogen receptors (CAPERα) via CRL4(DCAF15) mediated ubiquitination in human cancer cell lines...
April 24, 2017: Nature Chemical Biology
https://www.readbyqxmd.com/read/28429677/increased-expression-of-cullin-3-in-nasopharyngeal-carcinoma-and-knockdown-inhibits-proliferation-and-invasion
#5
Ruifang Zeng, Guolin Tan, Wei Li, Yanhong Ma
This study aimed to investigate the clinical significance of Cullin 3 expression in nasopharyngeal carcinoma (NPC), aswell as explore the regulatory mechanism of Cullin 3 underlying the growth and metastasis of NPC cells. Our findings showed that the expression levels of Cullin 3 expression were significantly increased in both NPC tissues and cell lines. A strong positive correlation was found between the Cullin 3 expression and Ki67-based proliferation index in NPC tissues. Moreover, Cullin 3 overexpression was correlated with the local relapse and distant metastasis in NPC patients...
April 18, 2017: Oncology Research
https://www.readbyqxmd.com/read/28428711/cullin-4a-is-associated-with-epithelial-to-mesenchymal-transition-and-poor-prognosis-in-perihilar-cholangiocarcinoma
#6
Tong-Jun Zhang, Dong Xue, Cheng-De Zhang, Ze-Dong Zhang, Qing-Ran Liu, Jian-Qiang Wang
AIM: To explore the functional role of cullin 4A (CUL4A), a core subunit of E3 ubiquitin ligase, in perihilar cholangiocarcinoma (PHCC). METHODS: The expression of CUL4A in PHCC cell lines was evaluated by Western blot and quantitative reverse transcription-polymerase chain reaction. Immunohistochemistry (IHC) was adopted to investigate the relationship between CUL4A expression and clinicopathological characteristics of PHCC. Univariate analysis and multivariate regression analysis were performed to analyze the risk factors related to overall survival (OS) and progression-free survival (PFS) of PHCC patients...
April 7, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28418860/targeting-the-overexpressed-roc1-induces-g2-cell-cycle-arrest-and-apoptosis-in-esophageal-cancer-cells
#7
Jingyang Zhang, Shuo Li, Zhaoyang Shang, Shan Lin, Peng Gao, Yi Zhang, Shuaiheng Hou, Saijun Mo, Wenbo Cao, Ziming Dong, Tao Hu, Ping Chen
Recent reports showed that regulator of Cullins-1 (ROC1) play an important role in tumor progression in a tumor-specific manner. However, the role and mechanism of ROC1 in esophageal cancer remains elusive. Here we demonstrated that ROC1 was overexpressed in esophageal squamous cell carcinomas, which was positive associated with poor prognosis of esophageal cancer patients. ROC1 knockdown significantly inhibited the growth of esophageal cancer cells in vitro and in vivo. Mechanistically, ROC1 silencing induced G2 cell cycle arrest and triggered apoptosis by accumulating the pro-apoptotic protein NOXA...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28401073/structural-insight-into-anaphase-promoting-complex-3-structure-and-docking-with-a-natural-inhibitory-compound
#8
Hamzeh Rahimi, Mohammad Ali Shokrgozar, Armin Madadkar-Sobhani, Reza Mahdian, Alireza Foroumadi, Morteza Karimipoor
BACKGROUND: Anaphase promoting complex (APC) is the biggest Cullin-RING E3 ligase and is very important in cell cycle control; many anti-cancer agents target this. APC controls the onset of chromosome separation and mitotic exit through securin and cyclin B degradation, respectively. Its APC3 subunit identifies the APC activators-Cdh1 and Cdc20. MATERIALS AND METHODS: The structural model of the APC3 subunit of APC was developed by means of computational techniques; the binding of a natural inhibitory compound to APC3 was also investigated...
2017: Advanced Biomedical Research
https://www.readbyqxmd.com/read/28392107/strigolactone-and-karrikin-independent-smxl-proteins-are-central-regulators-of-phloem-formation
#9
Eva-Sophie Wallner, Vadir López-Salmerón, Ilya Belevich, Gernot Poschet, Ilona Jung, Karin Grünwald, Iris Sevilem, Eija Jokitalo, Rüdiger Hell, Yrjö Helariutta, Javier Agustí, Ivan Lebovka, Thomas Greb
Plant stem cell niches, the meristems, require long-distance transport of energy metabolites and signaling molecules along the phloem tissue. However, currently it is unclear how specification of phloem cells is controlled. Here we show that the genes SUPPRESSOR OF MAX2 1-LIKE3 (SMXL3), SMXL4, and SMXL5 act as cell-autonomous key regulators of phloem formation in Arabidopsis thaliana. The three genes form an uncharacterized subclade of the SMXL gene family that mediates hormonal strigolactone and karrikin signaling...
April 24, 2017: Current Biology: CB
https://www.readbyqxmd.com/read/28388044/disclosing-the-interaction-of-carbonic-anhydrase-ix-with-cullin-associated-nedd8-dissociated-protein-1-by-molecular-modeling-and-integrated-binding-measurements
#10
Martina Buonanno, Emma Langella, Nicola Zambrano, Mariangela Succoio, Emanuele Sasso, Vincenzo Alterio, Anna Di Fiore, Annamaria Sandomenico, Claudiu T Supuran, Andrea Scaloni, Simona Maria Monti, Giuseppina De Simone
Human Carbonic Anhydrase (hCA) IX is a membrane-associated member of the CA enzyme family, involved in solid tumor acidification. This enzyme is a marker of tumor hypoxia and a prognostic factor for several human cancers. In a recent paper, we showed that CA IX interacts with cullin-associated NEDD8-dissociated protein 1 (CAND1), a nuclear protein involved in gene transcription and assembly of SCF ubiquitin ligase complexes. A functional role for this interaction was also identified, since lower CA IX levels were observed in cells with decreased CAND1 expression via shRNA-mediated interference...
April 19, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28383684/functional-variants-in-dcaf4-associated-with-lung-cancer-risk-in-european-populations
#11
Hongliang Liu, Zhensheng Liu, Yanru Wang, Thomas E Stinchcombe, Kouros Owzar, Younghun Han, Rayjean J Hung, Yonathan Brhane, John McLaughlin, Paul Brennan, Heike Bickeböller, Albert Rosenberger, Richard S Houlston, Neil Caporaso, Maria Teresa Landi, Irene Brüske, Angela Risch, Xifeng Wu, Yuanqing Ye, David C Christiani, Christopher I Amos, Qingyi Wei
Cullin-RING ubiquitin ligases (CRLs) responsible for substrate specificity of ubiquitination and play a key role in cell-cycle control and DNA damage response. In this study, we assessed associations between 16,599 SNPs in 115 CRL genes and lung cancer risk by using summary data of six published genome-wide association studies (GWASs) of 12,160 cases and 16,838 cases of European ancestry. As a result, we identified three independent SNPs in DCAF4 (rs117781739, rs12587742 and rs2240980) associated with lung cancer risk (odds ratio = 0...
April 5, 2017: Carcinogenesis
https://www.readbyqxmd.com/read/28377589/the-arabidopsis-cop9-signalosome-subunit-4-cns4-is-involved-in-adventitious-root-formation
#12
Daniel Ioan Pacurar, Monica Lacramioara Pacurar, Abdellah Lakehal, Andrea Mariana Pacurar, Alok Ranjan, Catherine Bellini
The COP9 signalosome (CSN) is an evolutionary conserved multiprotein complex that regulates many aspects of plant development by controlling the activity of CULLIN-RING E3 ubiquitin ligases (CRLs). CRLs ubiquitinate and target for proteasomal degradation a vast number of specific substrate proteins involved in many developmental and physiological processes, including light and hormone signaling and cell division. As a consequence of CSN pleiotropic function, complete loss of CSN activity results in seedling lethality...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28364216/prolactin-androgen-inducible-carboxypeptidase-d-increases-with-nitrotyrosine-and-ki67-for-breast-cancer-progression-in-vivo-and-upregulates-progression-markers-vegf-c-and-runx2-in-vitro
#13
Lynn N Thomas, Emily R Chedrawe, Penelope J Barnes, Catherine K L Too
PURPOSE: Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17β-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers...
March 31, 2017: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/28351980/transcription-factor-etv5-is-essential-for-the-maintenance-of-alveolar-type-ii-cells
#14
Zhen Zhang, Kim Newton, Sarah K Kummerfeld, Joshua Webster, Donald S Kirkpatrick, Lilian Phu, Jeffrey Eastham-Anderson, Jinfeng Liu, Wyne P Lee, Jiansheng Wu, Hong Li, Melissa R Junttila, Vishva M Dixit
Alveolar type II (AT2) cell dysfunction contributes to a number of significant human pathologies including respiratory distress syndrome, lung adenocarcinoma, and debilitating fibrotic diseases, but the critical transcription factors that maintain AT2 cell identity are unknown. Here we show that the E26 transformation-specific (ETS) family transcription factor Etv5 is essential to maintain AT2 cell identity. Deletion of Etv5 from AT2 cells produced gene and protein signatures characteristic of differentiated alveolar type I (AT1) cells...
April 11, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28341694/mineralocorticoid-receptor-and-nacl-transport-mechanisms-in-the-renal-distal-nephron
#15
Shigeru Shibata
A key role of aldosterone and mineralocorticoid receptor is to regulate fluid volume and K+ homeostasis in the body by acting on the renal distal nephron. Global responses of the kidney to elevated aldosterone levels are determined by the coordinate action of different constituent tubule cells, including principal cells, intercalated cells, and distal convoluted tubule cells. Recent studies on genetic mutations causing aldosterone overproduction have identified molecules involved in aldosterone biosynthesis in the adrenal gland, and there is also increasing evidence for mechanisms and signaling pathways regulating the balance between renal NaCl reabsorption and K+ secretion, the two major effects of aldosterone...
March 24, 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28315506/cullin-1-regulates-mg63-cell-proliferation-and-metastasis-and-is-a-novel-prognostic-marker-of-osteosarcoma
#16
Qinghua Cheng, Guoyong Yin
BACKGROUND: There is no reliable marker available for early detection, diagnostic confirmation or disease prognosis of osteosarcoma. Cullin-1 (CUL1) is a newly reported tumor-related gene, and we aimed to unravel its role in osteosarcoma. METHODS: We used immunohistochemistry to analyze the correlation between CUL1 expression and clinicopathological variables and patient survival. To evaluate the function of CUL1, a group of 28 osteosarcoma patients were recruited for this study...
December 5, 2016: International Journal of Biological Markers
https://www.readbyqxmd.com/read/28298444/scffbxo17-e3-ligase-modulates-inflammation-by-regulating-proteasomal-degradation-of-glycogen-synthase-kinase-3%C3%AE-in-lung-epithelia
#17
Tomeka Suber, Jianxin Wei, Anastasia M Jacko, Ina Nikolli, Yutong Zhao, Jing Zhao, Rama K Mallampalli
Glycogen synthase kinase-3β (GSK3β) has diverse biological roles including effects on cellular differentiation, migration, and inflammation. GSK3β phosphorylates proteins to generate phosphodegrons necessary for recognition by Skip-1/Cullin-1/F-box (SCF) E3 ubiquitin ligases leading to subsequent proteasomal degradation of these substrates. However, little is known regarding how GSK3β protein stability itself is regulated and how its stability may influence inflammation. Here we show that GSK3β is degraded by the ubiquitin-proteasome pathway in murine lung epithelial (MLE) cells through lysine 183 as an acceptor site for K48 polyubiquitination...
March 15, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28292928/cockayne-syndrome-b-protein-regulates-recruitment-of-the-elongin-a-ubiquitin-ligase-to-sites-of-dna-damage
#18
Juston C Weems, Brian D Slaughter, Jay R Unruh, Stefan Boeing, Shawn M Hall, Merry B McLaird, Takashi Yasukawa, Teijiro Aso, Jesper Q Svejstrup, Joan W Conaway, Ronald C Conaway
Elongin A performs dual functions as the transcriptionally active subunit of RNA polymerase II (Pol II) elongation factor Elongin and as the substrate recognition subunit of a Cullin-RING E3 ubiquitin ligase that ubiquitylates Pol II in response to DNA damage. Assembly of the Elongin A ubiquitin ligase and its recruitment to sites of DNA damage is a tightly regulated process induced by DNA-damaging agents and α-amanitin, a drug that induces Pol II stalling. In this study, we demonstrate (i) that Elongin A and the ubiquitin ligase subunit CUL5 associate in cells with the Cockayne syndrome B (CSB) protein and (ii) that this interaction is also induced by DNA-damaging agents and α-amanitin...
April 21, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28292897/inhibition-of-atherogenesis-by-the-cop9-signalosome-subunit-5-in-vivo
#19
Yaw Asare, Miriam Ommer, Florence A Azombo, Setareh Alampour-Rajabi, Marieke Sternkopf, Maryam Sanati, Marion J Gijbels, Corinna Schmitz, Dzmitry Sinitski, Pathricia V Tilstam, Hongqi Lue, André Gessner, Denise Lange, Johannes A Schmid, Christian Weber, Martin Dichgans, Joachim Jankowski, Ruggero Pardi, Menno P J de Winther, Heidi Noels, Jürgen Bernhagen
Constitutive photomorphogenesis 9 (COP9) signalosome 5 (CSN5), an isopeptidase that removes neural precursor cell-expressed, developmentally down-regulated 8 (NEDD8) moieties from cullins (thus termed "deNEDDylase") and a subunit of the cullin-RING E3 ligase-regulating COP9 signalosome complex, attenuates proinflammatory NF-κB signaling. We previously showed that CSN5 is up-regulated in human atherosclerotic arteries. Here, we investigated the role of CSN5 in atherogenesis in vivo by using mice with myeloid-specific Csn5 deletion...
March 28, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28290051/construction-of-a-comprehensive-protein-protein-interaction-map-for-vitiligo-disease-to-identify-key-regulatory-elements-a-systemic-approach
#20
Anvita Gupta Malhotra, Mohit Jha, Sudha Singh, Khushhali M Pandey
Vitiligo is an idiopathic disorder characterized by depigmented patches on the skin due to progressive loss of melanocytes. Several genetic, immunological, and pathophysiological investigations have established vitiligo as a polygenetic disorder with multifactorial etiology. However, no definite model explaining the interplay between these causative factors has been established hitherto. Therefore, we studied the disorder at the system level to identify the key proteins involved by exploring their molecular connectivity in terms of topological parameters...
March 13, 2017: Interdisciplinary Sciences, Computational Life Sciences
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