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Huan Chen, Zhaowei Xu, Xiahui Li, Yangyang Yang, Bowen Li, Yanan Li, Kangkai Xia, Jian Wang, Shujing Li, Miao Wang, Huijian Wu
α-catenin has been demonstrated to suppress several different types of cancers. Here we demonstrate that α-catenin is modified by SUMO protein, which covalently binds α-catenin at the carboxy terminus at lysine 870. Substitution of lysine 870 with arginine completely abolishes α-catenin SUMOylation. This modification can be removed by SENP1. However, α-catenin SUMOylation does not affect its stability and subcellular localization. In addition, we observed that the SUMOylation-deficient α-catenin mutant has a reduced interaction with IκBα which prevents subsequent ubiquitination of IκBα, and therefore a reduced suppression of expression of the NF-κB target genes TNF-α, IL-8, VEGF, and uPA...
March 13, 2018: Oncogenesis
Yuzhang Du, Guofang Hou, Hailong Zhang, Jinzhuo Dou, Jianfeng He, Yanming Guo, Lian Li, Ran Chen, Yanli Wang, Rong Deng, Jian Huang, Bin Jiang, Ming Xu, Jinke Cheng, Guo-Qiang Chen, Xian Zhao, Jianxiu Yu
The methyltransferase like 3 (METTL3) is a key component of the large N6-adenosine-methyltransferase complex in mammalian responsible for N6-methyladenosine (m6A) modification in diverse RNAs including mRNA, tRNA, rRNA, small nuclear RNA, microRNA precursor and long non-coding RNA. However, the characteristics of METTL3 in activation and post-translational modification (PTM) is seldom understood. Here we find that METTL3 is modified by SUMO1 mainly at lysine residues K177, K211, K212 and K215, which can be reduced by an SUMO1-specific protease SENP1...
February 28, 2018: Nucleic Acids Research
Nigus Ambaye, Chih-Hong Chen, Swati Khanna, Yi-Jia Li, Yuan Chen
Streptonigrin (CAS no. 3930-19-6) is a natural product shown to have anti tumor activities in clinical trials conducted in the 1960s-1970s. However, its use in clinical studies eventually faded, and the molecular mechanisms of streptonigrin anti-tumor effects remain poorly defined. Despite the lack of its current clinical use, efforts on its total synthesis have continued. Here, we show that streptonigrin binds and inhibits the SUMO-specific protease SENP1. NMR studies identified that streptonigrin binds to SENP1 on the surface where SUMO binds and disrupts SENP1-SUMO1 interaction...
February 26, 2018: Biochemistry
Deepesh Pandey, Yohei Nomura, Max C Rossberg, Daijiro Hori, Anil Bhatta, Gizem Keceli, Thorsten Leucker, Lakshmi Santhanam, Larissa A Shimoda, Dan Berkowitz, Lewis Romer
OBJECTIVE: KLF15 (Kruppel-like factor 15) has recently been shown to suppress activation of proinflammatory processes that contribute to atherogenesis in vascular smooth muscle, however, the role of KLF15 in vascular endothelial function is unknown. Arginase mediates inflammatory vasculopathy and vascular injury in pulmonary hypertension. Here, we tested the hypothesis that KLF15 is a critical regulator of hypoxia-induced Arg2 (arginase 2) transcription in human pulmonary microvascular endothelial cells (HPMEC)...
February 22, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Byeong Hyeok Choi, Changyan Chen, Mark Philips, Wei Dai
RAS proteins are GTPases that participate in multiple signal cascades, regulating crucial cellular processes including cell survival, proliferation, differentiation, and autophagy. Mutations or deregulated activities of RAS are frequently the driving force for oncogenic transformation and tumorigenesis. Given the important roles of the small ubiquitin-related modifier (SUMO) pathway in controlling the stability, activity, or subcellular localization of key cellular regulators, we investigated here whether RAS proteins are posttranslationally modified (i...
January 12, 2018: Oncotarget
E Ficulle, M D Shah Sufian, C Tinelli, M Corbo, M Feligioni
Protein activities and mechanisms related to aging has become a growing interest nowadays. Since SUMOylation is implicated in several cellular processes, its investigation related to senescence, aging and frailty is of high interest. In our study, wild type mice cortical lysates, synaptosomes and plasma have been processed to evaluate SUMOylation and SUMO machinery expression (Ubc9 and SENP1 enzymes) profile at different ages. In cortical lysates, SUMO-1ylation reached a peak at 6 months followed by a decrease; while in synaptosomes, it progressively increased till 18 months...
January 8, 2018: Neuroscience Letters
Hany A Abdel-Hafiz, Michelle L Dudevoir, Daniel Perez, Mohamed Abdel-Hafiz, Kathryn B Horwitz
Luminal breast cancers express estrogen (ER) and progesterone (PR) receptors, and respond to endocrine therapies. However, some ER+PR+ tumors display intrinsic or acquired resistance, possibly related to PR. Two PR isoforms, PR-A and PR-B, regulate distinct gene subsets that may differentially influence tumor fate. A high PR-A:PR-B ratio is associated with poor prognosis and tamoxifen resistance. We speculate that excessive PR-A marks tumors that will relapse early. Here we address mechanisms by which PR-A regulate transcription, focusing on SUMOylation...
January 2, 2018: Diseases (Basel)
Piotr Bialik, Katarzyna Woźniak
Sumoylation is one of the post-translational modifications of proteins, responsible for the regulation of many cellular processes, such as DNA replication and repair, transcription, signal transduction and nuclear transport. During sumoylation, SUMO proteins are covalently attached to the ε-amino group of lysine in target proteins via an enzymatic cascade that requires the sequential action of E1, E2 and E3 enzymes. An important aspect of sumoylation is its reversibility, which involves SUMO-specific proteases called SENPs...
December 8, 2017: Postȩpy Higieny i Medycyny Doświadczalnej
Lin-Shi Wu, Wei-Qing Qiu, Jian-Hua Sun, Jian Wang
To investigate whether SENP1 could play a regulating role in the liver fibrosis process, the Sprague-Dawley (SD) rats were used to establish the liver fibrosis rat models by intraperitoneally injecting with 1 ml/kg of 10% CCl4, while the control normal rats were injected with olive oil. Then confirmation experiments to verify the successful establishment of these models were conducted by detecting the cellular and lobular architecture, and liver function indexes using hematoxylin-eosin staining, Masson's trichrome staining and microplate method, respectively...
November 8, 2017: Biochemical and Biophysical Research Communications
Tsering Stobdan, Ali Akbari, Priti Azad, Dan Zhou, Orit Poulsen, Otto Appenzeller, Gustavo F Gonzales, Amalio Telenti, Emily H M Wong, Shubham Saini, Ewen F Kirkness, J Craig Venter, Vineet Bafna, Gabriel G Haddad
Human high-altitude (HA) adaptation or mal-adaptation is explored to understand the physiology, pathophysiology, and molecular mechanisms that underlie long-term exposure to hypoxia. Here, we report the results of an analysis of the largest whole-genome-sequencing of Chronic Mountain Sickness (CMS) and nonCMS individuals, identified candidate genes and functionally validated these candidates in a genetic model system (Drosophila). We used PreCIOSS algorithm that uses Haplotype Allele Frequency score to separate haplotypes carrying the favored allele from the noncarriers and accordingly, prioritize genes associated with the CMS or nonCMS phenotype...
December 1, 2017: Molecular Biology and Evolution
Priti Azad, Tsering Stobdan, Dan Zhou, Iain Hartley, Ali Akbari, Vineet Bafna, Gabriel G Haddad
About 1.2 to 33% of high-altitude populations suffer from Monge's disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes > 2500 m worldwide and are at risk for CMS. In this review, we focus on a human "experiment in nature" in various high-altitude locations in the world-namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years...
December 2017: Journal of Molecular Medicine: Official Organ of the "Gesellschaft Deutscher Naturforscher und Ärzte"
Xuetian Yue, Cen Zhang, Yuhan Zhao, Juan Liu, Alan W Lin, Victor M Tan, Justin M Drake, Lianxin Liu, Michael N Boateng, Jun Li, Zhaohui Feng, Wenwei Hu
Tumor suppressor p53 is frequently mutated in human cancer. Mutant p53 often promotes tumor progression through gain-of-function (GOF) mechanisms. However, the mechanisms underlying mutant p53 GOF are not well understood. In this study, we found that mutant p53 activates small GTPase Rac1 as a critical mechanism for mutant p53 GOF to promote tumor progression. Mechanistically, mutant p53 interacts with Rac1 and inhibits its interaction with SUMO-specific protease 1 (SENP1), which in turn inhibits SENP1-mediated de-SUMOylation of Rac1 to activate Rac1...
August 15, 2017: Genes & Development
Rubén Jiménez-Canino, Fabián Lorenzo-Díaz, Alex Odermatt, Matthew A Bailey, Dawn E W Livingstone, Frederic Jaisser, Nicolette Farman, Diego Alvarez de la Rosa
The enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) has an essential role in aldosterone target tissues, conferring aldosterone selectivity for the mineralocorticoid receptor (MR) by converting 11β-hydroxyglucocorticoids to inactive 11-ketosteroids. Congenital deficiency of 11β-HSD2 causes a form of salt-sensitive hypertension known as the syndrome of apparent mineralocorticoid excess. The disease phenotype, which ranges from mild to severe, correlates well with reduction in enzyme activity. Furthermore, polymorphisms in the 11β-HSD2 coding gene (HSD11B2) have been linked to high blood pressure and salt sensitivity, major cardiovascular risk factors...
November 1, 2017: Endocrinology
Andrea Pawellek, Ursula Ryder, Triin Tammsalu, Lewis J King, Helmi Kreinin, Tony Ly, Ronald T Hay, Richard C Hartley, Angus I Lamond
We have identified the plant biflavonoid hinokiflavone as an inhibitor of splicing in vitro and modulator of alternative splicing in cells. Chemical synthesis confirms hinokiflavone is the active molecule. Hinokiflavone inhibits splicing in vitro by blocking spliceosome assembly, preventing formation of the B complex. Cells treated with hinokiflavone show altered subnuclear organization specifically of splicing factors required for A complex formation, which relocalize together with SUMO1 and SUMO2 into enlarged nuclear speckles containing polyadenylated RNA...
September 8, 2017: ELife
Xiaowei Wang, Xiaoju Liang, Huan Liang, Bing Wang
Hypoxia is an element intrinsic to most solid-tumor microenvironments, including that of osteosarcoma (OS), and is associated with resistance to therapy, poor survival, and a malignant phenotype. The purpose of the present study was to investigate the role and underlying mechanism of SUMO-specific protease 1 (SENP1)/hypoxia-inducible factor-1α (HIF-1α) feedback loop in hypoxic microenvironment of OS. We observed that the expression of SENP1 was remarkably upregulated in OS cells. Additionally, there was a concomitant high expression of HIF-1α and SENP1 in MG-63 cells under a hypoxic microenvironment...
August 10, 2017: Journal of Cellular Biochemistry
Shu Tan, Boya Feng, Mingzhu Yin, Huanjiao Jenny Zhou, Ge Lou, Weidong Ji, Yonghao Li, Wang Min
BACKGROUND: Mammalian folliculogenesis, maturation of the ovarian follicles, require both growth factors derived from oocyte and surrounding cells, including stromal cells. However, the mechanism by which stromal cells and derived factors regulate oocyte development remains unclear. RESULTS: We observed that SENP1, a small ubiquitin-related modifier (SUMO)-specific isopeptidase, was expressed in sm22α-positive stromal cells of mouse ovary. The sm22α-positive stromal cells tightly associated with follicle maturation...
2017: Cell & Bioscience
Xiaolong Zhu, Sha Ding, Cong Qiu, Yanna Shi, Lin Song, Yueyue Wang, Yuewen Wang, Jinying Li, Yiran Wang, Yi Sun, Lingfeng Qin, Jun Chen, Michael Simons, Wang Min, Luyang Yu
RATIONALE: The highly conserved NOTCH (neurogenic locus notch homolog protein) signaling pathway functions as a key cell-cell interaction mechanism controlling cell fate and tissue patterning, whereas its dysregulation is implicated in a variety of developmental disorders and cancers. The pivotal role of endothelial NOTCH in regulation of angiogenesis is widely appreciated; however, little is known about what controls its signal transduction. Our previous study indicated the potential role of post-translational SUMO (small ubiquitin-like modifier) modification (SUMOylation) in vascular disorders...
September 1, 2017: Circulation Research
Guo-Qiang Zhou, Fu Han, Zhi-Liang Shi, Liang Yu, Xue-Feng Li, Cheng Yu, Cheng-Long Shen, Dai-Wei Wan, Xin-Quo Zhu, Rui Li, Song-Bing He
Dysregulation of SUMO-specific protease 1(SENP1) expression has been reported in several kinds of cancer, including human colorectal and prostate cancers, proposing SENP1 as a oncogene with a critical role in cancer progression. MiR-133a-3p has been reported as a tumor suppressor in several malignant neoplasias. However, the precise molecular mechanisms underlying its role in colorectal cancer remain largely unknown. The aim of this work is to investigate the relationship between miR-133a-3p and SENP1 in colorectal cancer cells...
July 26, 2017: Oncology Research
Huaize Liu, Sen Yan, Jie Ding, Ting-Ting Yu, Steven Y Cheng
The transcriptional output of the Sonic Hedgehog morphogenic pathway is orchestrated by three Krüppel family transcription factors, Gli1 to -3, which undergo extensive posttranslational modifications, including ubiquitination and SUMOylation. Here, we report that the sentrin-specific peptidase SENP1 is the specific deSUMOylation enzyme for Gli1. We show that SUMOylation stabilizes Gli1 by competing with ubiquitination at conserved lysine residues and that SUMOylated Gli1 is enriched in the nucleus, suggesting that SUMOylation is a nuclear localization signal for Gli1...
September 15, 2017: Molecular and Cellular Biology
Long Zhang, Feng Xie, Juan Zhang, Peter Ten Dijke, Fangfang Zhou
Nuclear receptor NR4A1 has been implicated as a key regulator in a wide range of pathophysiological responses. As an immediate early response gene, NR4A1 can be rapidly and potently induced by a variety of stimuli. Its induction is followed by its rapid degradation, but the mechanism by which NR4A1 is degraded remains poorly understood. Here we show that nuclear receptor NR4A1 is sumoylated by SUMO2/3. Upon poly-SUMO modification, NR4A1 can be targeted by the SUMO-dependent E3 ubiquitin ligase RNF4 for polyubiquitination and subsequent degradation...
September 2017: Cell Death and Differentiation
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