Journal articles on the topic 'Ubiquitin-Specific Peptidase 1'
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Raimondi, Marzia, Daniela Cesselli, Carla Di Loreto, Francesco La Marra, Claudio Schneider, and Francesca Demarchi. "USP1 (ubiquitin specific peptidase 1) targets ULK1 and regulates its cellular compartmentalization and autophagy." Autophagy 15, no. 4 (October 29, 2018): 613–30. http://dx.doi.org/10.1080/15548627.2018.1535291.
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Zhang, Jinghui, Chenchang Liu, and Guofeng You. "Ubiquitin-specific peptidase 8 regulates the trafficking and stability of the human organic anion transporter 1." Biochimica et Biophysica Acta (BBA) - General Subjects 1864, no. 12 (December 2020): 129701. http://dx.doi.org/10.1016/j.bbagen.2020.129701.
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Shanmugam, Ilanchezhian, Mohammad Abbas, Farhan Ayoub, Susan Mirabal, Manal Bsaili, Erin K. Caulder, David M. Weinstock, Alan E. Tomkinson, Robert Hromas, and Monte Shaheen. "Ubiquitin-specific Peptidase 20 Regulates Rad17 Stability, Checkpoint Kinase 1 Phosphorylation and DNA Repair by Homologous Recombination." Journal of Biological Chemistry 289, no. 33 (June 12, 2014): 22739–48. http://dx.doi.org/10.1074/jbc.m114.550459.
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Attaix, Didier, Sophie Ventadour, Audrey Codran, Daniel Béchet, Daniel Taillandier, and Lydie Combaret. "The ubiquitin–proteasome system and skeletal muscle wasting." Essays in Biochemistry 41 (October 1, 2005): 173–86. http://dx.doi.org/10.1042/bse0410173.
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The ubiquitin–proteasome system (UPS) is believed to degrade the major contractile skeletal muscle proteins and plays a major role in muscle wasting. Different and multiple events in the ubiquitination, deubiquitination and proteolytic machineries are responsible for the activation of the system and subsequent muscle wasting. However, other proteolytic enzymes act upstream (possibly m-calpain, cathepsin L, and/or caspase 3) and downstream (tripeptidyl-peptidase II and aminopeptidases) of the UPS, for the complete breakdown of the myofibrillar proteins into free amino acids. Recent studies have identified a few critical proteins that seem necessary for muscle wasting {i.e. the MAFbx (muscle atrophy F-box protein, also called atrogin-1) and MuRF-1 [muscle-specific RING (really interesting new gene) finger 1] ubiquitin–protein ligases}. The characterization of their signalling pathways is leading to new pharmacological approaches that can be useful to block or partially prevent muscle wasting in human patients.
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Nakae, Aya, Michiko Kodama, Toru Okamoto, Makoto Tokunaga, Hiroko Shimura, Kae Hashimoto, Kenjiro Sawada, et al. "Ubiquitin specific peptidase 32 acts as an oncogene in epithelial ovarian cancer by deubiquitylating farnesyl-diphosphate farnesyltransferase 1." Biochemical and Biophysical Research Communications 552 (May 2021): 120–27. http://dx.doi.org/10.1016/j.bbrc.2021.03.049.
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Ogawa, Masahiro, Tomoya Kitakaze, Naoki Harada, and Ryoichi Yamaji. "Female-specific regulation of skeletal muscle mass by USP19 in young mice." Journal of Endocrinology 225, no. 3 (April 21, 2015): 135–45. http://dx.doi.org/10.1530/joe-15-0128.
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17β-estradiol (E2) is thought to be responsible for sex-specific differences in skeletal muscle mass. The biological function of E2 is exerted through its binding to estrogen receptor α (ERα). The expression of ubiquitin-specific peptidase 19 (USP19) is upregulated during muscle atrophy and by E2-activated ERα. Here, we investigated the involvement of USP19 in sex difference in muscle mass in young mice. Knockdown of USP19 in hindlimb muscles increased the mass and fiber size in soleus muscle in females but not males. Using Usp19 promoter reporter constructs, a functional half-estrogen response element (hERE) was identified in intron 1 of Usp19. ERα bound to hERE in an E2-dependent manner in C2C12 myoblasts and in soleus muscle in ovariectomized (OVX) female mice. Furthermore, under normal physiological conditions, ERα bound to hERE in soleus muscle only in females. In contrast, administration of E2 resulted in increased Usp19 mRNA expression, decreased muscle mass, and recruitment of ERα to hERE in soleus muscle in males. Knockdown of ERα in hindlimb muscles decreased Usp19 mRNA expression and increased the mass of soleus muscle only in females. Knockdown of USP19 resulted in increased levels of ubiquitin conjugates in soleus muscle in females. OVX increased the levels of ubiquitin conjugates and administration of E2 decreased OVX-induced levels of ubiquitin conjugates. These results demonstrate that in soleus muscle in young female mice under physiological conditions, E2 upregulates USP19 expression through ERα and consequently leads to decreases in ubiquitin conjugates and muscle mass.
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Yu, Zhongxia, Hui Song, Mutian Jia, Jintao Zhang, Wenwen Wang, Qi Li, Lining Zhang, and Wei Zhao. "USP1–UAF1 deubiquitinase complex stabilizes TBK1 and enhances antiviral responses." Journal of Experimental Medicine 214, no. 12 (November 14, 2017): 3553–63. http://dx.doi.org/10.1084/jem.20170180.
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Optimal activation of TANK-binding kinase 1 (TBK1) is crucial for initiation of innate antiviral immunity and maintenance of immune homeostasis. Although several E3 ubiquitin ligases have been reported to regulate TBK1 activation by mediating its polyubiquitination, the functions of deubiquitinase on TBK1 activity remain largely unclear. Here, we identified a deubiquitinase complex, which is formed by ubiquitin specific peptidase 1 (USP1) and USP1-associated factor 1 (UAF1), as a viral infection–induced physiological enhancer of TBK1 expression. USP1–UAF1 complex enhanced TLR3/4 and RIG-I–induced IFN regulatory factor 3 (IRF3) activation and subsequent IFN-β secretion. Mechanistically, USP1 and UAF1 bound to TBK1, removed its K48-linked polyubiquitination, and then reversed the degradation process of TBK1. Furthermore, we found that ML323, a specific USP1–UAF1 inhibitor, attenuated IFN-β expression and enhanced viral replication both in vitro and in vivo. Therefore, our results outline a novel mechanism for the control of TBK1 activity and suggest USP1–UAF1 complex as a potential target for the prevention of viral diseases.
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Hu, Bin, Chunhua Ge, and Chunqing Zhu. "Ubiquitin-specific peptidase 18 negatively regulates and inhibits lipopolysaccharide-induced sepsis by targeting transforming growth factor-β-activated kinase 1 activity." International Immunology 33, no. 9 (June 11, 2021): 461–68. http://dx.doi.org/10.1093/intimm/dxab029.
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Abstract Sepsis is an inflammatory disease with exacerbated inflammation at early stages. Inflammatory cytokines play critical roles in the pathophysiology of sepsis. Ubiquitin-specific peptidase 18 (USP18), a deubiquitinating enzyme, has been shown to modulate transforming growth factor-β-activated kinase 1 (TAK1) activity. However, the precise role of USP18 in sepsis is not clear. Here, we investigated the potential effect of USP18 on inflammation in sepsis. We generated mice with USP18 or/and TAK1 deficiency in macrophages (USP18MKO mice, TAK1MKO mice and USP18MKO-TAK1MKO mice) and established a lipopolysaccharide (LPS)-induced sepsis model in mice. Bone marrow-derived macrophages were isolated from wild-type (WT), USP18MKO or TAK1MKO mice and treated with LPS or CpG, and the expression of cytokines including IL-6, IL-10, IL-1β and tumor necrosis factor α (TNF-α) was measured. The activation of NF-κB, ERK and p38 signaling pathways and ubiquitination of TAK1 were detected. We induced sepsis in WT, USP18MKO, TAK1MKO or USP18MKO-TAK1MKO mice and evaluated the survival rate, lung pathology and inflammatory cytokine levels in serum. Macrophages deficient in USP18 produced significantly increased IL-6, IL-1β and TNF-α post-LPS or -CpG stimulation. Macrophages deficient in USP18 had promoted activation of NF-κB, p38 and ERK, and increased ubiquitination of TAK1. Mice with TAK1 deficiency in macrophages had increased survival rates, decreased immune cell infiltration in lung and decreased pro-inflammatory cytokines in serum. In contrast, mice with USP18 deficiency in macrophages had decreased survival rates, increased cell infiltration in lung and increased pro-inflammatory cytokines in serum. USP18 alleviated LPS-induced sepsis by inhibiting TAK1 activity.
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Yasunaga, J., F. C. Lin, X. Lu, and K. T. Jeang. "Ubiquitin-Specific Peptidase 20 Targets TRAF6 and Human T Cell Leukemia Virus Type 1 Tax To Negatively Regulate NF- B Signaling." Journal of Virology 85, no. 13 (April 27, 2011): 6212–19. http://dx.doi.org/10.1128/jvi.00079-11.
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Jingjing, Wu, Guo Wenzheng, Wen Donghua, Hou Guangyu, Zhou Aiping, and Wu Wenjuan. "Deubiquitination and stabilization of programmed cell death ligand 1 by ubiquitin-specific peptidase 9, X-linked in oral squamous cell carcinoma." Cancer Medicine 7, no. 8 (July 10, 2018): 4004–11. http://dx.doi.org/10.1002/cam4.1675.
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Meuwissen, Marije E. C., Rachel Schot, Sofija Buta, Grétel Oudesluijs, Sigrid Tinschert, Scott D. Speer, Zhi Li, et al. "Human USP18 deficiency underlies type 1 interferonopathy leading to severe pseudo-TORCH syndrome." Journal of Experimental Medicine 213, no. 7 (June 20, 2016): 1163–74. http://dx.doi.org/10.1084/jem.20151529.
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Pseudo-TORCH syndrome (PTS) is characterized by microcephaly, enlarged ventricles, cerebral calcification, and, occasionally, by systemic features at birth resembling the sequelae of congenital infection but in the absence of an infectious agent. Genetic defects resulting in activation of type 1 interferon (IFN) responses have been documented to cause Aicardi-Goutières syndrome, which is a cause of PTS. Ubiquitin-specific peptidase 18 (USP18) is a key negative regulator of type I IFN signaling. In this study, we identified loss-of-function recessive mutations of USP18 in five PTS patients from two unrelated families. Ex vivo brain autopsy material demonstrated innate immune inflammation with calcification and polymicrogyria. In vitro, patient fibroblasts displayed severely enhanced IFN-induced inflammation, which was completely rescued by lentiviral transduction of USP18. These findings add USP18 deficiency to the list of genetic disorders collectively termed type I interferonopathies. Moreover, USP18 deficiency represents the first genetic disorder of PTS caused by dysregulation of the response to type I IFNs. Therapeutically, this places USP18 as a promising target not only for genetic but also acquired IFN-mediated CNS disorders.
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Singh, Rahul, Sonali Deshmukh, Ashwani Kumar, Venuka Durani Goyal, and Ravindra D. Makde. "Crystal structure of XCC3289 from Xanthomonas campestris: homology with the N-terminal substrate-binding domain of Lon peptidase." Acta Crystallographica Section F Structural Biology Communications 76, no. 10 (September 16, 2020): 488–94. http://dx.doi.org/10.1107/s2053230x20011875.
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LonA peptidase is a major component of the protein quality-control mechanism in both prokaryotes and the organelles of eukaryotes. Proteins homologous to the N-terminal domain of LonA peptidase, but lacking its other domains, are conserved in several phyla of prokaryotes, including the Xanthomonadales order. However, the function of these homologous proteins (LonNTD-like proteins) is not known. Here, the crystal structure of the LonNTD-like protein from Xanthomonas campestris (XCC3289; UniProt Q8P5P7) is reported at 2.8 Å resolution. The structure was solved by molecular replacement and contains one polypeptide in the asymmetric unit. The structure was refined to an R free of 29%. The structure of XCC3289 consists of two domains joined by a long loop. The N-terminal domain (residues 1–112) consists of an α-helix surrounded by β-sheets, whereas the C-terminal domain (residues 123–193) is an α-helical bundle. The fold and spatial orientation of the two domains closely resembles those of the N-terminal domains of the LonA peptidases from Escherichia coli and Mycobacterium avium. The structure is also similar to that of cereblon, a substrate-recognizing component of the E3 ubiquitin ligase complex. The N-terminal domains of both LonA and cereblon are known to be involved in specific protein–protein interactions. This structural analysis suggests that XCC3289 and other LonNTD-like proteins might also be capable of such protein–protein interactions.
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Xu, Gufeng, Xiaojie Tan, Hongmei Wang, Wenjing Sun, Yi Shi, Susan Burlingame, Xue Gu, et al. "Ubiquitin-specific Peptidase 21 Inhibits Tumor Necrosis Factor α-induced Nuclear Factor κB Activation via Binding to and Deubiquitinating Receptor-interacting Protein 1." Journal of Biological Chemistry 285, no. 2 (November 12, 2009): 969–78. http://dx.doi.org/10.1074/jbc.m109.042689.
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Zhang, Yana, and Deyu Fang. "USP22 controls iNKT immunity partially through MED1-mediated suppression of target-specific histone H2A monoubiquitination." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 78.1. http://dx.doi.org/10.4049/jimmunol.204.supp.78.1.
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Abstract The development and functions of CD1d-restricted iNKT cells are critical for both innate and adaptive immunity. While the ubiquitin pathway has been shown to regulate iNKT cell development and functions, the deubiquitinase involved in this process has not been identified. Herein we found that the ubiquitin-specific peptidase 22 (USP22) is highly expressed in iNKT cells during their early developmental stage I. USP22-deficiency blocked the transition from stage I to II during iNKT cell development in a cell-intrinsic manner. In addition, genetic USP22 suppression largely diminishes IL-17-producing iNKT17 and IFN-g-producing iNKT1 differentiation but favors IL-4 producing iNKT2 polarization. In contrast, genetic USP22 suppression did not alter conventional CD4 T cell clonal expansion and differentiation. At the molecular level, USP22 interacts with the Mediator of RNA polymerase II transcription subunit 1 (MED1), a transcription co-activator involved in iNKT cell development. Interestingly, while interacting with MED1, USP22 does not function as a deubiquitinase to suppress MED1 ubiquitination for its stabilization. Instead, USP22 enhances MED1 functions for IL-2Rb and T-bet gene expression through deubiquitinating histone H2A but not H2B mono-ubiquitination. Therefore, our study revealed USP22-mediated histone H2A deubiquitination fine-tunes MED1 transcriptional activation as a previously unappreciated molecular mechanism to control iNKT development and functions.
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Yu, Wen-Chun, Ren-Yeong Huang, and Tz-Chong Chou. "Oligo-Fucoidan Improves Diabetes-Induced Renal Fibrosis via Activation of Sirt-1, GLP-1R, and Nrf2/HO-1: An In Vitro and In Vivo Study." Nutrients 12, no. 10 (October 8, 2020): 3068. http://dx.doi.org/10.3390/nu12103068.
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Fucoidan extracted from brown algae has multiple beneficial functions. In this study, we investigated the effects of low-molecular-weight fucoidan (oligo-FO) on renal fibrosis under in vitro and in vivo diabetic conditions, and its molecular mechanisms. Advanced glycation product (AGE)-stimulated rat renal proximal tubular epithelial cells (NRK-52E) and diabetic mice induced by high-fat diet and intraperitoneal injection of streptozotocin and nicotinamide were used. Oligo-FO treatment significantly inhibited anti-high mobility group box 1 (HMGB1)/RAGE/ anti-nuclear factor-kappa B (NF-κB)/transforming growth factor-β1 (TGF-β1)/TGF-β1R/Smad 2/3/fibronectin signaling pathway and HIF-1α activation in AGE-stimulated NRK-52E cells. Conversely, the expression and activity of Sirt-1; the levels of ubiquitin-specific peptidase 22 (USP22), p-AMPK, glucagon-like peptide-1 receptor (GLP-1R), and heme oxygenase-1 (HO-1); and Nrf2 activation were remarkably increased by oligo-FO in AGE-stimulated cells. However, the above effects of oligo-FO were greatly diminished by inhibiting Sirt-1, HO-1, or GLP-1R activity. Similar changes of these pro-fibrotic genes in the kidney and a marked attenuation of renal injury and dysfunction were observed in oligo-FO-treated diabetic mice. These findings indicated that the inhibitory effects of the oligo-FO on diabetes-evoked renal fibrosis are mediated by suppressing TGF-β1-activated pro-fibrogenic processes via Sirt-1, HO-1, and GLP-1R dependence. Collectively, fucoidan-containing foods or supplements may be potential agents for ameliorating renal diseases due to excessive fibrosis.
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Park, Jung-Eun, Thị Xuân Thùy Trần, Nayoung Park, Jeonghun Yeom, Kyunggon Kim, and Min-Ji Kang. "The Function of Drosophila USP14 in Endoplasmic Reticulum Stress and Retinal Degeneration in a Model for Autosomal Dominant Retinitis Pigmentosa." Biology 9, no. 10 (October 12, 2020): 332. http://dx.doi.org/10.3390/biology9100332.
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Endoplasmic reticulum (ER) stress and its adaptive cellular response, the unfolded protein response (UPR), are involved in various diseases including neurodegenerative diseases, metabolic diseases, and even cancers. Here, we analyzed the novel function of ubiquitin-specific peptidase 14 (USP14) in ER stress. The overexpression of Drosophila USP14 protected the cells from ER stress without affecting the proteasomal activity. Null Hong Kong (NHK) and alpha-1-antitrypsin Z (ATZ) are ER-associated degradation substrates. The degradation of NHK, but not of ATZ, was delayed by USP14. USP14 restored the levels of rhodopsin-1 protein in a Drosophila model for autosomal dominant retinitis pigmentosa and suppressed the retinal degeneration in this model. In addition, we observed that proteasome complex is dynamically reorganized in response to ER stress in human 293T cells. These findings suggest that USP14 may be a therapeutic strategy in diseases associated with ER stress.
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Witty, James, Elisa Aguilar-Martinez, and Andrew D. Sharrocks. "SENP1 participates in the dynamic regulation of Elk-1 SUMOylation." Biochemical Journal 428, no. 2 (May 13, 2010): 247–54. http://dx.doi.org/10.1042/bj20091948.
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The modification of proteins with SUMO (small ubiquitin-related modifier) plays an important role in determining their functional properties. Importantly though, SUMOylation is a highly dynamic process enabling transient responses to be elicited. This dynamism is controlled by two competing conjugating and deconjugating activities. The latter activity is mediated by the SENP [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase] family of SUMO-specific proteases. The transcription factor Elk-1 [ETS (E twenty-six)-like 1] undergoes rapid de-SUMOylation following cellular stimulation with growth factors, and this contributes to its conversion from a SUMO-dependent repressor into a potent transcriptional activator. In the present study we demonstrate an important role for SENP1 in the de-SUMOylation of Elk-1, and therefore an integral role in determining the Elk-1-dependent transcriptional programme. Among the SENPs, Elk-1 preferentially forms a complex with SENP1. This preferential binding is reflected by the higher efficiency of SENP1 in promoting Elk-1 transactivation. Moreover, depletion of SENP1 causes a reciprocal effect and reduces the transactivation properties of Elk-1. Partial redundancy of function with SENP2 is revealed by combinatorial knockdown studies. Importantly, depletion of SENP1 also reduces the activation of the Elk-1 target gene c-FOS. Taken together, these results therefore reveal an important role for SENP1 in the regulation of Elk-1-mediated gene expression in response to mitogenic signalling cues.
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Mussell, Ashley, He Shen, Yanmin Chen, Michalis Mastri, Kevin H. Eng, Wiam Bshara, Costa Frangou, and Jianmin Zhang. "USP1 Regulates TAZ Protein Stability Through Ubiquitin Modifications in Breast Cancer." Cancers 12, no. 11 (October 23, 2020): 3090. http://dx.doi.org/10.3390/cancers12113090.
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The Hippo signaling pathway is an evolutionarily conserved pathway that was initially discovered in Drosophila melanogaster and was later found to have mammalian orthologues. The key effector proteins in this pathway, YAP/TAZ, are often dysregulated in cancer, leading to a high degree of cell proliferation, migration, metastasis and cancer stem cell populations. Due to these malignant phenotypes it is important to understand the regulation of YAP/TAZ at the protein level. Using an siRNA library screen of deubiquitinating enzymes (DUBs), we identified ubiquitin specific peptidase 1 (USP1) as a novel TAZ (WWTR1) regulator. We demonstrated that USP1 interacts with TAZ and increases TAZ protein stability. Conversely, loss of function of USP1 reduces TAZ protein levels through increased poly-ubiquitination, causing a decrease in cell proliferation and migration of breast cancer cells. Moreover, we showed a strong positive correlation between USP1 and TAZ in breast cancer patients. Our findings facilitate the attainment of better understanding of the crosstalk between these pathways and may lead to potential therapeutic interventions for breast cancer patients.
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Kishi, Kasane, Aya Uchida, Hinako M. Takase, Hitomi Suzuki, Masamichi Kurohmaru, Naoki Tsunekawa, Masami Kanai-Azuma, Stephen A. Wood, and Yoshiakira Kanai. "Spermatogonial deubiquitinase USP9X is essential for proper spermatogenesis in mice." Reproduction 154, no. 2 (August 2017): 135–43. http://dx.doi.org/10.1530/rep-17-0184.
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USP9X (ubiquitin-specific peptidase 9, X chromosome) is the mammalian orthologue of Drosophila deubiquitinase fat facets that was previously shown to regulate the maintenance of the germ cell lineage partially through stabilizing Vasa, one of the widely conserved factors crucial for gametogenesis. Here, we demonstrate that USP9X is expressed in the gonocytes and spermatogonia in mouse testes from newborn to adult stages. By using Vasa-Cre mice, germ cell-specific conditional deletion of Usp9x from the embryonic stage showed no abnormality in the developing testes by 1 week and no appreciable defects in the undifferentiated and differentiating spermatogonia at postnatal and adult stages. Interestingly, after 2 weeks, Usp9x-null spermatogenic cells underwent apoptotic cell death at the early spermatocyte stage, and then, caused subsequent aberrant spermiogenesis, which resulted in a complete infertility of Usp9x conditional knockout male mice. These data provide the first evidence of the crucial role of the spermatogonial USP9X during transition from the mitotic to meiotic phases and/or maintenance of early meiotic phase in Usp9x conditional knockout testes.
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Chang, Tsung-Hsien, Songxiao Xu, Prafullakumar Tailor, Tomohiko Kanno, and Keiko Ozato. "The Small Ubiquitin-like Modifier-Deconjugating Enzyme Sentrin-Specific Peptidase 1 Switches IFN Regulatory Factor 8 from a Repressor to an Activator during Macrophage Activation." Journal of Immunology 189, no. 7 (August 31, 2012): 3548–56. http://dx.doi.org/10.4049/jimmunol.1201104.
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Watson, Christopher Mark, Laura A. Crinnion, Lindsay Gleghorn, William G. Newman, Rajkumar Ramesar, Peter Beighton, and Gillian A. Wallis. "Identification of a mutation in the ubiquitin-fold modifier 1-specific peptidase 2 gene, UFSP2, in an extended South African family with Beukes hip dysplasia." South African Medical Journal 105, no. 7 (September 21, 2015): 558. http://dx.doi.org/10.7196/samjnew.7917.
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Zheng, Lewei, Qian Yang, Chengxin Li, Gaoran Xu, Qianqian Yuan, Jinxuan Hou, and Gaosong Wu. "Ubiquitin-Specific Peptidase 8 Modulates Cell Proliferation and Induces Cell Cycle Arrest and Apoptosis in Breast Cancer by Stabilizing Estrogen Receptor Alpha." Journal of Oncology 2023 (January 6, 2023): 1–16. http://dx.doi.org/10.1155/2023/8483325.
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Breast cancer (BC) is the most common neoplastic and lethal malignancy in women. Although antiendocrine therapy is the main treatment for estrogen receptor alpha (ERα)-positive BC, the development of resistance is a major clinical complication. In this study, we aimed to explore the role of ubiquitin-specific peptidase 8 (USP8) in ERα signaling and identify potential targets for endocrine resistance. Public databases were used to analyze USP8 expression, prognosis, clinical characteristics, and immune cell infiltration. Immunohistochemistry and western blot assays were used to detect protein levels and ERα signaling. Quantitative reverse transcription-PCR was used to measure ERα target gene expression. The cell counting kit-8, wound-healing, clone formation, and Transwell assays were used to investigate the effects of USP8 depletion or inhibition on cell proliferation, migration, and invasion. An immunofluorescence assay was used for localizing USP8 and ERα, and a protein stability assay was performed for detecting the degradation of ERα protein. The cell cycle and apoptosis were assessed using flow cytometry. USP8 was highly expressed in the luminal subtype of BC and was associated with poor prognosis. The infiltration levels of many immune cells were positively correlated with USP8 expression. Depletion of USP8 dramatically decreased the ERα signaling activity and weakened the proliferation, migration, and invasion capabilities of BC cells. USP8 knockdown markedly induced apoptosis and cell cycle arrest ( G 0 / G 1 ). Colocalization analysis and protein stability assays indicated a probable mechanism by which USP8 regulates ERα. Our study demonstrates that USP8 might be crucial in BC development and may be considered a potential target for treating ER-positive BC malignancies in vitro.
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Wu, Xingxin, Tao Tan, and Qiang Xu. "Metastatic colorectal cancer cells harness nonsense-mediated mRNA decay for immune evasion." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 242.17. http://dx.doi.org/10.4049/jimmunol.204.supp.242.17.
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Abstract Immunosuppression microenvironment allows primary tumor growth, while tumor-inherent factors that bring about immune evasion during metastasis remain elusive. Here, we observed a stronger nonsense-mediated mRNA decay (NMD) activity with a higher expression of up-frameshift protein 1 (UPF1) in colorectal cancer (CRC) metastasis than in matched primary cancer cells. In metastatic CRC SW620 cells, the higher UPF1 expression was found to arise from the increased stability of UPF1 by ubiquitin specific peptidase 10 (USP10)-mediated deubiquitination. In contrast, in primary CRC SW480 cells, autophagy promotes proteolysis of ubiquitinated UPF1 and inhibits NMD activity. Interestingly, in SW620 cells NMD selectively controlled a cluster of immune-related genes including ICAM1. Furthermore, NMD inhibition exposed SW620 cells but not SW480 cells to natural killer (NK) cell-mediated cytolysis that depended on ICAM1. Conclusion NMD activity can be recommissioned in CRC metastasis cells to escape from NK-dependent immune surveillance, and inhibiting NMD to boost anti-tumor immunity could be a novel strategy to treat CRC metastasis.
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Yongganmg, Liu, and Gao Shizheng. "A novel porcine gene, USP7, differentially expressed in the musculus longissimus from Wujin and Large White pigs." Czech Journal of Animal Science 55, No. 1 (January 25, 2010): 37–41. http://dx.doi.org/10.17221/1709-cjas.
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The mRNA differential display technique was performed to investigate differences in the gene expression in the <I>musculus longissimus</I> from Wujin and Large White pigs. A fragment of one differentially expressed gene was isolated and sequenced. A complete cDNA sequence was obtained using the rapid amplification of cDNA ends (RACE) method. The sequence prediction analysis revealed that the open reading frame of this gene encodes a protein of 1 103 amino acids, which is homologous with the ubiquitin specific peptidase 7 (<I>USP7</I>) of four species, rat (identity 98%), human (98%), mouse (98%) and chicken (95%), so it can be defined as the porcine <I>USP7</I> gene. The differences in the USP7 gene expression in muscles from Wujin and Large White pigs were confirmed using semi-quantitative RT-PCR. The gene expression analysis in eight tissues of a Wujin × Large White cross showed that <I>USP7</I> was expressed in all the tissues, except for fat.
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Shang, Zesen, Jiao Zhao, Qi Zhang, Cheng Cao, Shanshan Tian, Kai Zhang, Ling Liu, Lei Shi, Na Yu, and Shangda Yang. "USP9X-mediated deubiquitination of B-cell CLL/lymphoma 9 potentiates Wnt signaling and promotes breast carcinogenesis." Journal of Biological Chemistry 294, no. 25 (May 9, 2019): 9844–57. http://dx.doi.org/10.1074/jbc.ra119.007655.
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Hyperactivation of the canonical Wnt-signaling pathway is a prominent feature of a number of human malignancies. Transcriptional activation of this signaling cascade depends on the formation of the β-catenin–B-cell CLL/lymphoma 9 (BCL9)–pygopus (PYGO) family plant homeodomain finger 1 complex, yet how the assembly of this complex is regulated remains to be investigated. Here, using MCF-7, HeLa, HEK293T, MDA–MB-231, and Sf9 cells, along with immunoblotting and immunofluorescence, nano-HPLC–MS/MS, deubiquitination, immunoprecipitation, and chromatin immunoprecipitation (ChIP) assays, we report that BCL9 physically associates with a protein deubiquitinase, ubiquitin-specific peptidase 9, X-linked (USP9X), and that USP9X removes Lys-63–linked polyubiquitin on Lys-212 of BCL9. Importantly, the USP9X-mediated BCL9 deubiquitination facilitated the formation of the β-catenin–BCL9–PYGO complex, thereby potentiating the transcriptional activation of Wnt/β-catenin target genes. We also show that USP9X-mediated BCL9 deubiquitination promotes the proliferation and invasion of breast cancer cells. Together, these results uncover USP9X as a deubiquitinase of BCL9, implicating USP9X in Wnt/β-catenin signaling and breast carcinogenesis.
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Chung, Sung Soo, Byung Yong Ahn, Min Kim, Jun Ho Kho, Hye Seung Jung, and Kyong Soo Park. "SUMO modification selectively regulates transcriptional activity of peroxisome-proliferator-activated receptor γ in C2C12 myotubes." Biochemical Journal 433, no. 1 (December 15, 2010): 155–61. http://dx.doi.org/10.1042/bj20100749.
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PPAR (peroxisome-proliferator-activated receptor) γ, a nuclear receptor, can be conjugated with SUMO (small ubiquitin-like modifier), which results in the negative regulation of its transcriptional activity. In the present study, we tested whether de-SUMOylation of PPARγ affects the expression of PPARγ target genes in mouse muscle cells and investigated the mechanism by which de-SUMOylation increases PPARγ transcriptional activity. We found that the SUMO-specific protease SENP2 [SUMO1/sentrin/SMT3 (suppressor of mif two 3 homologue 1)-specific peptidase 2] effectively de-SUMOylates PPARγ–SUMO conjugates. Overexpression of SENP2 in C2C12 cells increased the expression of some PPARγ target genes, such as FABP3 (fatty-acid-binding protein 3) and CD36 (fatty acid translocase), both in the absence and presence of rosiglitazone. In contrast, overexpression of SENP2 did not affect the expression of another PPARγ target gene ADRP (adipose differentiation-related protein). De-SUMOylation of PPARγ increased ChIP (chromatin immunoprecipitation) of both a recombinant PPRE (PPAR-response element) and endogenous PPREs of the target genes CD36 and FABP3, but ChIP of the PPRE in the ADRP promoter was not affected by SENP2 overexpression. In conclusion, these results indicate that SENP2 de-SUMOylates PPARγ in myotubes, and de-SUMOylation of PPARγ selectively increases the expression of some PPARγ target genes.
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Liang, Fengshan, Adam S. Miller, Caroline Tang, David Maranon, Elizabeth A. Williamson, Robert Hromas, Claudia Wiese, Weixing Zhao, Patrick Sung, and Gary M. Kupfer. "The DNA-binding activity of USP1-associated factor 1 is required for efficient RAD51-mediated homologous DNA pairing and homology-directed DNA repair." Journal of Biological Chemistry 295, no. 24 (April 29, 2020): 8186–94. http://dx.doi.org/10.1074/jbc.ra120.013714.
Full textAbstract:
USP1-associated factor 1 (UAF1) is an integral component of the RAD51-associated protein 1 (RAD51AP1)–UAF1-ubiquitin-specific peptidase 1 (USP1) trimeric deubiquitinase complex. This complex acts on DNA-bound, monoubiquitinated Fanconi anemia complementation group D2 (FANCD2) protein in the Fanconi anemia pathway of the DNA damage response. Moreover, RAD51AP1 and UAF1 cooperate to enhance homologous DNA pairing mediated by the recombinase RAD51 in DNA repair via the homologous recombination (HR) pathway. However, whereas the DNA-binding activity of RAD51AP1 has been shown to be important for RAD51-mediated homologous DNA pairing and HR-mediated DNA repair, the role of DNA binding by UAF1 in these processes is unclear. We have isolated mutant UAF1 variants that are impaired in DNA binding and tested them together with RAD51AP1 in RAD51-mediated HR. This biochemical analysis revealed that the DNA-binding activity of UAF1 is indispensable for enhanced RAD51 recombinase activity within the context of the UAF1–RAD51AP1 complex. In cells, DNA-binding deficiency of UAF1 increased DNA damage sensitivity and impaired HR efficiency, suggesting that UAF1 and RAD51AP1 have coordinated roles in DNA binding during HR and DNA damage repair. Our findings show that even though UAF1's DNA-binding activity is redundant with that of RAD51AP1 in FANCD2 deubiquitination, it is required for efficient HR-mediated chromosome damage repair.
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Pariano, Marilena, Stefania Pieroni, Antonella De Luca, Rossana G. Iannitti, Monica Borghi, Matteo Puccetti, Stefano Giovagnoli, et al. "Anakinra Activates Superoxide Dismutase 2 to Mitigate Inflammasome Activity." International Journal of Molecular Sciences 22, no. 12 (June 18, 2021): 6531. http://dx.doi.org/10.3390/ijms22126531.
Full textAbstract:
Inflammasomes are powerful cytosolic sensors of environmental stressors and are critical for triggering interleukin-1 (IL-1)-mediated inflammatory responses. However, dysregulation of inflammasome activation may lead to pathological conditions, and the identification of negative regulators for therapeutic purposes is increasingly being recognized. Anakinra, the recombinant form of the IL-1 receptor antagonist, proved effective by preventing the binding of IL-1 to its receptor, IL-1R1, thus restoring autophagy and dampening NLR family pyrin domain containing 3 (NLRP3) activity. As the generation of mitochondrial reactive oxidative species (ROS) is a critical upstream event in the activation of NLRP3, we investigated whether anakinra would regulate mitochondrial ROS production. By profiling the activation of transcription factors induced in murine alveolar macrophages, we found a mitochondrial antioxidative pathway induced by anakinra involving the manganese-dependent superoxide dismutase (MnSOD) or SOD2. Molecularly, anakinra promotes the binding of SOD2 with the deubiquitinase Ubiquitin Specific Peptidase 36 (USP36) and Constitutive photomorphogenesis 9 (COP9) signalosome, thus increasing SOD2 protein longevity. Functionally, anakinra and SOD2 protects mice from pulmonary oxidative inflammation and infection. On a preclinical level, anakinra upregulates SOD2 in murine models of chronic granulomatous disease (CGD) and cystic fibrosis (CF). These data suggest that protection from mitochondrial oxidative stress may represent an additional mechanism underlying the clinical benefit of anakinra and identifies SOD2 as a potential therapeutic target.
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García-Santisteban, Iraia, Sonia Bañuelos, and Jose A. Rodríguez. "A global survey of CRM1-dependent nuclear export sequences in the human deubiquitinase family." Biochemical Journal 441, no. 1 (December 14, 2011): 209–17. http://dx.doi.org/10.1042/bj20111300.
Full textAbstract:
The mechanisms that regulate the nucleocytoplasmic localization of human deubiquitinases remain largely unknown. The nuclear export receptor CRM1 binds to specific amino acid motifs termed NESs (nuclear export sequences). By using in silico prediction and experimental validation of candidate sequences, we identified 32 active NESs and 78 inactive NES-like motifs in human deubiquitinases. These results allowed us to evaluate the performance of three programs widely used for NES prediction, and to add novel information to the recently redefined NES consensus. The novel NESs identified in the present study reveal a subset of 22 deubiquitinases bearing motifs that might mediate their binding to CRM1. We tested the effect of the CRM1 inhibitor LMB (leptomycin B) on the localization of YFP (yellow fluorescent protein)- or GFP (green fluorescent protein)-tagged versions of six NES-bearing deubiquitinases [USP (ubiquitin-specific peptidase) 1, USP3, USP7, USP21, CYLD (cylindromatosis) and OTUD7B (OTU-domain-containing 7B)]. YFP–USP21 and, to a lesser extent, GFP–OTUD7B relocated from the cytoplasm to the nucleus in the presence of LMB, revealing their nucleocytoplasmic shuttling capability. Two sequence motifs in USP21 had been identified during our survey as active NESs in the export assay. Using site-directed mutagenesis, we show that one of these motifs mediates USP21 nuclear export, whereas the second motif is not functional in the context of full-length USP21.
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Wu, Suwen, Yutong Cui, Huanqiang Zhao, Xirong Xiao, Lili Gong, Huangfang Xu, Qiongjie Zhou, Duan Ma, and Xiaotian Li. "Trophoblast Exosomal UCA1 Induces Endothelial Injury through the PFN1-RhoA/ROCK Pathway in Preeclampsia: A Human-Specific Adaptive Pathogenic Mechanism." Oxidative Medicine and Cellular Longevity 2022 (September 15, 2022): 1–19. http://dx.doi.org/10.1155/2022/2198923.
Full textAbstract:
Preeclampsia is regarded as an evolution-related disease that has only been observed in humans and our closest relatives, and the important factor contributing to its pathogenesis is endothelial dysregulation secondary to a stressed placenta. Hypoxia-inducible factor 1 subunit alpha (HIF1α), a highly conserved molecule in virtually all mammals, is regarded as a crucial regulator of the hypoxia adaptation and evolution. Persistent high expression of HIF1α in the placenta is one of the pathogenic mechanisms of preeclampsia. Therefore, human-specific molecules should link increased HIF1α to preeclampsia. We reported that urothelial cancer associated 1 (UCA1) is a potential mediator because it is a human-specific long noncoding RNA (lncRNA) that is upregulated in placental tissues and maternal serum from women with preeclampsia and is regulated by HIF1α. The cellular HIF1α-UCA1 pathway promoted the adaptation of trophoblasts to hypoxia by inducing vascular endothelial growth factor (VEGF) secretion and changes in the levels of key enzymes in glycolysis. On the other hand, circulating exosomal UCA1 secreted from stressed trophoblasts induced vascular endothelial dysfunction, especially excess ROS production, as measured by exosome extraction and a coculture system. At the molecular level, UCA1 physically bound to ubiquitin-specific peptidase 14 (USP14), which is a deubiquitinating enzyme, and UCA1 functioned as a scaffold to recruit USP14 to profilin 1 (PFN1), an actin-binding protein contributing to endothelial abnormalities and vascular diseases. This ternary complex inhibited the ubiquitination-dependent degradation of PFN1 and prolonged its half-life, further activating the RhoA/Rho-kinase (ROCK) pathway to induce ROS production in endothelial cells. Taken together, these observations suggest a role for the evolution-related UCA1 in the HIF1α-induced adaptive pathogenic mechanism of preeclampsia, promoting the survival of hypoxic trophoblasts and injuring maternal endothelial cells.
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Metzendorf, Christoph, Katharina Wineberger, Jenny Rausch, Antonio Cigliano, Kristin Peters, Baodong Sun, Daniela Mennerich, et al. "Transcriptomic and Proteomic Analysis of Clear Cell Foci (CCF) in the Human Non-Cirrhotic Liver Identifies Several Differentially Expressed Genes and Proteins with Functions in Cancer Cell Biology and Glycogen Metabolism." Molecules 25, no. 18 (September 10, 2020): 4141. http://dx.doi.org/10.3390/molecules25184141.
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Clear cell foci (CCF) of the liver are considered to be pre-neoplastic lesions of hepatocellular adenomas and carcinomas. They are hallmarked by glycogen overload and activation of AKT (v-akt murine thymoma viral oncogene homolog)/mTOR (mammalian target of rapamycin)-signaling. Here, we report the transcriptome and proteome of CCF extracted from human liver biopsies by laser capture microdissection. We found 14 genes and 22 proteins differentially expressed in CCF and the majority of these were expressed at lower levels in CCF. Using immunohistochemistry, the reduced expressions of STBD1 (starch-binding domain-containing protein 1), USP28 (ubiquitin-specific peptidase 28), monad/WDR92 (WD repeat domain 92), CYB5B (Cytochrome b5 type B), and HSPE1 (10 kDa heat shock protein, mitochondrial) were validated in CCF in independent specimens. Knockout of Stbd1, the gene coding for Starch-binding domain-containing protein 1, in mice did not have a significant effect on liver glycogen levels, indicating that additional factors are required for glycogen overload in CCF. Usp28 knockout mice did not show changes in glycogen storage in diethylnitrosamine-induced liver carcinoma, demonstrating that CCF are distinct from this type of cancer model, despite the decreased USP28 expression. Moreover, our data indicates that decreased USP28 expression is a novel factor contributing to the pre-neoplastic character of CCF. In summary, our work identifies several novel and unexpected candidates that are differentially expressed in CCF and that have functions in glycogen metabolism and tumorigenesis.
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Wu, Danyang, Rong Yuan, Lian Zhang, and Meng Sun. "USP13 reduces septic mediated cardiomyocyte oxidative stress and inflammation by inducing Nrf2." Allergologia et Immunopathologia 51, no. 2 (March 1, 2023): 160–67. http://dx.doi.org/10.15586/aei.v51i2.813.
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Background: Sepsis is a common cardiovascular complication that can cause heart damage. The regulatory role of ubiquitin-specific peptidase 13 (USP13) on erythroid 2–related factor 2 (Nrf2) has been reported, but its regulatory role in septic cardiomyopathy remains unclear.Methods: The Sprague Dawley (SD) rat model of septic myocardial injury was constructed by lipopolysaccharides (LPS). The serum lactate dehydrogenase (LDH) and creatine kinase (CK) levels were detected, the mRNA and protein expression levels of Nrf2 and USP13 in tissues were detected by real-time quantitative reverse transcription PCR (qRT-PCR) and western blot (WB), and the expression of USP13 at the treatment time of 3 h, 6 h, and 12 h was alsodetected. The cell viability and USP13, Nrf-2 and heme oxygenase-1 (HO-1) expression levels of H9C2-treated cells by LPS and the oxidative stress level and inflammatory response of H9C2 cells were detected by enzyme-linked immunosorbent assay (ELISA) and WB.Results: The results showed that USP13 was downregulated in septic myocardial injury tissues, and the Nrf2 level was increased in vitro after the cells were treated with LPS. Overexpression of USP13 further induced Nrf2 to reduce apoptosis, oxidative stress, and expression of inflammatory factors.Conclusion: In conclusion, this study demonstrated that USP13 was downregulated in septic myocardial injury tissues, and USP13 overexpression increased Nrf2 levels and reduced apoptosis. Further studies showed that USP13 reduced LPS-induced oxidative stress and inflammation by inducing Nrf2.
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Suzuki, Keisuke, Junko Shibato, Randeep Rakwal, Masahiko Takaura, Ryotaro Hotta, and Yoshinori Masuo. "Biomarkers in the Rat Hippocampus and Peripheral Blood for an Early Stage of Mental Disorders Induced by Water Immersion Stress." International Journal of Molecular Sciences 24, no. 4 (February 5, 2023): 3153. http://dx.doi.org/10.3390/ijms24043153.
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It is difficult to evaluate the pre-symptomatic state of mental disorders and prevent its onset. Since stress could be a trigger of mental disorders, it may be helpful to identify stress-responsive biomarkers (stress markers) for the evaluation of stress levels. We have so far performed omics analyses of the rat brain and peripheral blood after various kinds of stress and have found numerous factors that respond to stress. In this study, we investigated the effects of relatively moderate stress on these factors in the rat to identify stress marker candidates. Adult male Wistar rats underwent water immersion stress for 12 h, 24 h, or 48 h. Stress caused weight loss and elevated serum corticosterone levels, and alterations regarded as anxiety and/or fear-like behaviors. Reverse-transcription PCR and Western blot analyses revealed significant alterations in the expressions of hippocampal genes and proteins by the stress for no longer than 24 h, such as mitogen-activated protein kinase phosphatase 1 (MKP-1), CCAAT/enhancer-binding protein delta (CEBPD), small ubiquitin-like modifier proteins 1/sentrin-specific peptidase 5 (SENP5), matrix metalloproteinase-8 (MMP-8), kinase suppressor of Ras 1 (KSR1), and MKP-1, MMP-8, nerve growth factor receptor (NGFR). Similar alterations were observed in three genes (MKP-1, CEBPD, MMP-8) in the peripheral blood. The present results strongly suggest that these factors may serve as stress markers. The correlation of these factors in the blood and brain may enable the evaluation of stress-induced changes in the brain by blood analysis, which will contribute to preventing the onset of mental disorders.
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Dhingra, Rimpy, Inna Rabinovich-Nikitin, Sonny Rothman, Matthew Guberman, Hongying Gang, Victoria Margulets, Davinder S. Jassal, et al. "Proteasomal Degradation of TRAF2 Mediates Mitochondrial Dysfunction in Doxorubicin-Cardiomyopathy." Circulation 146, no. 12 (September 20, 2022): 934–54. http://dx.doi.org/10.1161/circulationaha.121.058411.
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Background: Cytokines such as tumor necrosis factor-α (TNFα) have been implicated in cardiac dysfunction and toxicity associated with doxorubicin (DOX). Although TNFα can elicit different cellular responses, including survival or death, the mechanisms underlying these divergent outcomes in the heart remain cryptic. The E3 ubiquitin ligase TRAF2 (TNF receptor associated factor 2) provides a critical signaling platform for K63-linked polyubiquitination of RIPK1 (receptor interacting protein 1), crucial for nuclear factor-κB (NF-κB) activation by TNFα and survival. Here, we investigate alterations in TNFα–TRAF2–NF-κB signaling in the pathogenesis of DOX cardiotoxicity. Methods: Using a combination of in vivo (4 weekly injections of DOX 5 mg·kg −1 ·wk −1 ) in C57/BL6J mice and in vitro approaches (rat, mouse, and human inducible pluripotent stem cell–derived cardiac myocytes), we monitored TNFα levels, lactate dehydrogenase, cardiac ultrastructure and function, mitochondrial bioenergetics, and cardiac cell viability. Results: In contrast to vehicle-treated mice, ultrastructural defects, including cytoplasmic swelling, mitochondrial perturbations, and elevated TNFα levels, were observed in the hearts of mice treated with DOX. While investigating the involvement of TNFα in DOX cardiotoxicity, we discovered that NF-κB was readily activated by TNFα. However, TNFα-mediated NF-κB activation was impaired in cardiac myocytes treated with DOX. This coincided with loss of K63- linked polyubiquitination of RIPK1 from the proteasomal degradation of TRAF2. Furthermore, TRAF2 protein abundance was markedly reduced in hearts of patients with cancer treated with DOX. We further established that the reciprocal actions of the ubiquitinating and deubiquitinating enzymes cellular inhibitors of apoptosis 1 and USP19 (ubiquitin-specific peptidase 19), respectively, regulated the proteasomal degradation of TRAF2 in DOX-treated cardiac myocytes. An E3-ligase mutant of cellular inhibitors of apoptosis 1 (H588A) or gain of function of USP19 prevented proteasomal degradation of TRAF2 and DOX-induced cell death. Furthermore, wild-type TRAF2, but not a RING finger mutant defective for K63-linked polyubiquitination of RIPK1, restored NF-κB signaling and suppressed DOX-induced cardiac cell death. Last, cardiomyocyte-restricted expression of TRAF2 (cardiac troponin T–adeno-associated virus 9–TRAF2) in vivo protected against mitochondrial defects and cardiac dysfunction induced by DOX. Conclusions: Our findings reveal a novel signaling axis that functionally connects the cardiotoxic effects of DOX to proteasomal degradation of TRAF2. Disruption of the critical TRAF2 survival pathway by DOX sensitizes cardiac myocytes to TNFα-mediated necrotic cell death and DOX cardiotoxicity.
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Kwakkel, J., H. C. van Beeren, M. T. Ackermans, M. C. Platvoet-ter Schiphorst, E. Fliers, W. M. Wiersinga, and A. Boelen. "Skeletal muscle deiodinase type 2 regulation during illness in mice." Journal of Endocrinology 203, no. 2 (August 5, 2009): 263–70. http://dx.doi.org/10.1677/joe-09-0118.
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We have previously shown that skeletal muscle deiodinase type 2 (D2) mRNA (listed as Dio2 in MGI Database) is upregulated in an animal model of acute illness. However, human studies on the expression of muscle D2 during illness report conflicting data. Therefore, we evaluated the expression of skeletal muscle D2 and D2-regulating factors in two mouse models of illness that differ in timing and severity of illness: 1) turpentine-induced inflammation, and 2) Streptococcus pneumoniae infection. During turpentine-induced inflammation, D2 mRNA and activity increased compared to pair-fed controls, most prominently at day 1 and 2, whereas after S. pneumoniae infection D2 mRNA decreased. We evaluated the association of D2 expression with serum thyroid hormones, (de-)ubiquitinating enzymes ubiquitin-specific peptidase 33 and WD repeat and SOCS box-containing 1 (Wsb1), cytokine expression and activation of inflammatory pathways and cAMP pathway. During chronic inflammation the increased muscle D2 expression is associated with the activation of the cAMP pathway. The normalization of D2 5 days after turpentine injection coincides with increased Wsb1 and tumor necrosis factor α expression. Muscle interleukin-1β (Il1b) expression correlated with decreased D2 mRNA expression after S. pneumoniae infection. In conclusion, muscle D2 expression is differentially regulated during illness, probably related to differences in the inflammatory response and type of pathology. D2 mRNA and activity increases in skeletal muscle during the acute phase of chronic inflammation compared to pair-fed controls probably due to activation of the cAMP pathway. In contrast, muscle D2 mRNA decreases 48 h after a severe bacterial infection, which is associated with local Il1b mRNA expression and might also be due to diminished food-intake.
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Bai, Mixue, Yingying Che, Kun Lu, and Lin Fu. "Analysis of deubiquitinase OTUD5 as a biomarker and therapeutic target for cervical cancer by bioinformatic analysis." PeerJ 8 (June 30, 2020): e9146. http://dx.doi.org/10.7717/peerj.9146.
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OTU deubiquitinase 5 (OTUD5), as a member of the ovarian tumor protease (OTU) family, was previously reported to play important roles in DNA repair and immunity. However, little is known about its function in tumors. Cervical cancer is a malignant tumor that seriously endangers the lives of women. Here, we found that low expression of OTUD5 in cervical cancer is associated with poor prognosis. Its expression is associated with tumor stage, metastatic nodes and tumor subtypes such as those related to the phosphatidylinositol–3–kinase (PI3K)–AKT signaling, epithelial-mesenchymal transition (EMT) and hormones. In addtion, we analyzed the coexpressed genes, related miRNAs, transcription factors, kinases, E3s and interacting proteins of OTUD5. We demonstrated that OTUD5 affects the expression levels of WD repeat domain 45 (WDR45), ubiquitin-specific peptidase 11 (USP11), GRIP1 associated protein 1 (GRIPAP1) and RNA binding motif protein 10 (RBM10). Moreover, hsa-mir-137, hsa-mir-1913, hsa-mir-937, hsa-mir-607, hsa-mir-3149 and hsa-mir-144 may inhibit the expression of OTUD5. Furthermore, we performed enrichment analysis of 22 coexpressed genes, 33 related miRNAs and 30 interacting proteins. In addition to ubiquitination and immunology related processes, they also participate in Hippo signaling, insulin signaling, EMT, histone methylation and phosphorylation kinase binding. Our study for the first time analyzed the expression of OTUD5 in cervical cancer and its relationship with clinicopathology and provided new insights for further study of its regulatory mechanism in tumors.
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Zhou, Jiangqiao, Tao Qiu, Tianyu Wang, Zhongbao Chen, Xiaoxiong Ma, Long Zhang, and Jilin Zou. "USP4 deficiency exacerbates hepatic ischaemia/reperfusion injury via TAK1 signalling." Clinical Science 133, no. 2 (January 2019): 335–49. http://dx.doi.org/10.1042/cs20180959.
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Abstract Ubiquitin-specific peptidase 4 (USP4) protein is a type of deubiquitination enzyme that is correlated with many important biological processes. However, the function of USP4 in hepatic ischaemia/reperfusion (I/R) injury remains unknown. The aim of the present study was to explore the role of USP4 in hepatic I/R injury. USP4 gene knockout mice and primary hepatocytes were used to construct hepatic I/R models. The effect of USP4 on hepatic I/R injury was examined via pathological and molecular analyses. Our results indicated that USP4 was significantly up-regulated in liver of mice subjected to hepatic I/R injury. USP4 knockout mice exhibited exacerbated hepatic I/R injury, as evidenced by enhanced liver inflammation via the nuclear factor κB (NF-κB) signalling pathway and increased hepatocyte apoptosis. Additionally, USP4 overexpression inhibited hepatocyte inflammation and apoptosis on hepatic I/R stimulation. Mechanistically, our study demonstrates that USP4 deficiency exerts its detrimental effects on hepatic I/R injury by inducing activation of the transforming growth factor β-activated kinase 1 (TAK1)/JNK signalling pathways. TAK1 was required for USP4 function in hepatic I/R injury as TAK1 inhibition abolished USP4 function in vitro. In conclusion, our study demonstrates that USP4 deficiency plays a detrimental role in hepatic I/R injury by promoting activation of the TAK1/JNK signalling pathways. Modulation of this axis may be a novel strategy to alleviate the pathological process of hepatic I/R injury.
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Yang, Yanli, Jun Li, and Yinghua Geng. "Exosomes derived from chronic lymphocytic leukaemia cells transfer miR-146a to induce the transition of mesenchymal stromal cells into cancer-associated fibroblasts." Journal of Biochemistry 168, no. 5 (July 10, 2020): 491–98. http://dx.doi.org/10.1093/jb/mvaa064.
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Abstract Chronic lymphocytic leukaemia (CLL) is the most prevalent leukaemia and remains incurable. Mesenchymal stem cells (MSCs) can promote tumour progression by differentiating into cancer-associated fibroblasts (CAFs). However, the mechanisms by which tumour cells induce the transition of MSCs to CAFs are still largely undefined. Exosomes can regulate recipient cellular function by mediating intracellular communication. This study aimed to investigate whether CLL cells regulate the transition of bone marrow-derived MSCs (BM-MSCs) to CAFs via exosomal miR-146a delivery. The exosomes were isolated from CLL cell line MEC-1 (CLL-Exo) and then co-cultured with BM-MSCs. The expression of α-smooth muscle actin (α-SMA) and fibroblast-activated protein (FAP) were determined by immunofluorescence, quantitative real-time polymerase chain reaction and western blot. A luciferase reporter assay was performed to verify whether ubiquitin-specific peptidase 16 (USP16) was a target of miR-146a. CLL-Exo treatment up-regulated miR-146a and down-regulated expression of CAF markers (α-SMA and FAP) and USP16. The inducing effect of CLL-Exo on CAF marker expression was compromised when miR-146a expression was inhibited in CLL-Exo. USP16 was confirmed as a direct target of miR-146a and USP16 overexpression in BM-MSCs abrogated the CLL-Exo-mediated up-regulation of CAF markers. Collectively, CLL-Exo delivered miR-146a into BM-MSCs where miR-146a mediated transition of BM-MSCs into CAFs by targeting USP16.
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Xiang, Yijin, Shaoyan Zhang, Jia Lu, Wen Zhang, Min Cai, Dongze Qiu, and Dingfang Cai. "USP9X promotes LPS-induced pulmonary epithelial barrier breakdown and hyperpermeability by activating an NF-κBp65 feedback loop." American Journal of Physiology-Cell Physiology 317, no. 3 (September 1, 2019): C534—C543. http://dx.doi.org/10.1152/ajpcell.00094.2019.
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NF-κB is a central regulator of inflammatory and immune responses and has been shown to regulate transcription of several inflammatory factors as well as promote acute lung injury. However, the regulation of NF-κB signaling in acute lung injury has yet to be investigated. Human pulmonary alveolar epithelial cells (HPAEpiC) were treated with LPS to establish an acute lung injury model in vitro in which LPS stimulation resulted in pulmonary epithelial barrier breakdown and hyperpermeability. Cell viability was measured by CCK-8, and the transepithelial permeability was examined by measurement of transepithelial electrical resistance (TEER) and the transepithelial flux. Expression of ubiquitin-specific peptidase 9 X-linked (USP9X), zonula occludens (ZO-1), occludin and NF-κBp65, and the secretion of TNF-α and IL-1β were measured by Western blotting and ELISA, respectively. For in vivo studies, mice were intraperitoneally injected with LPS and/or NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC). Lung tissues were harvested for hematoxylin-eosin staining and Western blotting, and bronchoalveolar lavage fluid (BALF) was harvested for ELISA. We found that treatment with LPS in HPAEpiC inhibited cell viability and induced the expression of USP9X. Interestingly, knockdown of USP9X and treatment with PDTC suppressed LPS-induced HPAEpiC injury. USP9X overexpression promoted NF-κB activation, while NF-κB inactivation inhibited USP9X transcription and HPAEpiC injury induced by USP9X overexpression. Furthermore, LPS also induced the expression of USP9X in lungs, which was inhibited by PDTC. Taken together, these results demonstrate a critical role of USP9X-NF-κBp65 loop in mediating LPS-induced acute lung injury and may serve as a potential therapeutic target in acute lung injury.
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Plaué, S., S. Muller, and M. H. van Regenmortel. "A branched, synthetic octapeptide of ubiquitinated histone H2A as target of autoantibodies." Journal of Experimental Medicine 169, no. 5 (May 1, 1989): 1607–17. http://dx.doi.org/10.1084/jem.169.5.1607.
Full textAbstract:
Two peptides of eight (T2) and 10 (T1) residues corresponding to the branched moiety of ubiquitinated histone H2A have been synthesized and used for raising specific antibodies in rabbits. Antisera to peptide T1 reacted in ELISA with T1 and with H2A but not with ubiquitin; antisera to peptide T2 reacted with T2 but not with H2A or ubiquitin. When tested in immunoblotting, both peptide antisera reacted with ubiquitinated H2A but not with unconjugated H2A or with ubiquitin. Sera from patients with systemic lupus erythematosus (SLE) were shown previously to react with ubiquitin in ELISA and immunoblotting. When tested for their ability to react in ELISA with synthetic peptides T1 and T2, 96% of the SLE sera (diluted 1:500) that recognized ubiquitin also reacted with peptide T2. Of the SLE sera that did not react with ubiquitin, only 13% possessed antibodies able to bind peptide T2. Antibodies from seven SLE sera, purified on a T2-immunoadsorbent column, were also able to react either with H2A, and in three cases also with ubiquitin.
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Niederkorn, Madeline, Melinda Varney, Molly A. Smith, Ruhikanta A. Meetei, and Daniel T. Starczynowski. "Tifab, a Del(5q) MDS/AML Gene, Regulates USP15 Activity and p53." Blood 128, no. 22 (December 2, 2016): 1130. http://dx.doi.org/10.1182/blood.v128.22.1130.1130.
Full textAbstract:
Abstract Interstitial deletion of a single copy of chromosome 5q is the most frequent cytogenetic alteration in Myelodysplastic Syndromes (MDS), which results in reduced dosage of numerous genes. TRAF-interacting protein with forkhead-associated domain B (TIFAB) resides within the proximal commonly-deleted region on band 5q31.1, and belongs to a family of forkhead-associated domain proteins. TIFAB is deleted in nearly all reported cases of del(5q) MDS and AML. As expected, TIFAB expression is significantly lower in CD34+ and BM mononuclear cells isolated from MDS patients with del(5q) as compared with cells from MDS patients diploid at chr 5q. Recently we have shown that hematopoietic-specific deletion of Tifab results in progressive BM and blood defects, including aberrant HSPC proportions, altered myeloid differentiation, and progressive cytopenia (Varney and Niederkorn et al., JEM 2015). Approximately 10% of mice transplanted with Tifab KO HSPCs develop a BM failure with neutrophil dysplasia and cytopenia. Gene expression analysis of Tifab KO lineage-Sca1+cKit+ (LSK) cells identified dysregulation of immune-related signatures, and hypersensitivity to Toll-like receptor stimulation. To investigate the molecular function of TIFAB, we performed a tandem-affinity tag purification and mass-spectrometry analysis of TIFAB complexes in a del(5q) AML cell line (HL60), and identified unique TIFAB-interacting proteins. The top interacting candidate was an ubiquitin-specific peptidase (USP), USP15. USPs play a major role in ubiquitin-dependent processes including DNA damage response signaling, protein degradation, and kinase activation. Specifically, USP15 has been shown to promote p53 degradation via deubiquitination and stabilization of its major negative regulator, MDM2. Through biochemical assays and a series of deletion mutants, we confirmed that TIFAB interacts with USP15. Moreover, we find that TIFAB enhances the deubiquitination of USP15 substrates, including MDM2 and histone 2B. To examine whether TIFAB directly regulates USP15 DUB activity, we performed in vitro deubiquitination assays in a cell-free system using fluorescent reporter di-ubiquitin substrates with purified USP15. We found that the addition of purified TIFAB increases the rate of USP15 catalytic activity on both lysine (K)48 and K63-linked di-ubiquitins in a dose-dependent manner. Collectively, these findings indicated that the USP15-TIFAB interaction leads to increased USP15 activity. USP15 stabilizes MDM2 via its DUB function, and MDM2 is known to bind and inhibit p53. Moreover, p53 is implicated in the pathogenesis of del(5q) MDS: 1) BM cells from murine models and BM from del(5q) patients exhibit increased p53 activity, which is thought to contribute to ineffective hematopoiesis and anemia; and 2) del(5q) MDS patients often acquire concurrent TP53 mutations that result in rapid transformation to AML and poor treatment response. To examine the effects of TIFAB on p53 function, we examined p53 target genes in TIFAB-overexpressing and -deficient cells. Gene expression profiling and qRT-PCR analysis of Tifab KOHSPCs revealed significant upregulation of p53 regulatory genes. In contrast, overexpression of TIFAB in a p53-competent cell line reduced the expression of p53 target gene, p21. Collectively, our findings identify a novel role for TIFAB as an activating adapter of USP15 and mediator of p53 activity. These findings have important implications in the potential role of TIFAB and p53 signaling in the pathogenesis of del(5q) MDS and transformation to AML. Disclosures No relevant conflicts of interest to declare.
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de Oyarzabal, Eleane, Lourdes García-García, Claudia Rangel-Escareño, Leticia Ferreyra-Reyes, Lorena Orozco, María Teresa Herrera, Claudia Carranza, et al. "Expression of USP18 and IL2RA Is Increased in Individuals Receiving Latent Tuberculosis Treatment with Isoniazid." Journal of Immunology Research 2019 (December 6, 2019): 1–13. http://dx.doi.org/10.1155/2019/1297131.
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Background. The treatment of latent tuberculosis infection (LTBI) in individuals at risk of reactivation is essential for tuberculosis control. However, blood biomarkers associated with LTBI treatment have not been identified. Methods. Blood samples from tuberculin skin test (TST) reactive individuals were collected before and after one and six months of isoniazid (INH) therapy. Peripheral mononuclear cells (PBMC) were isolated, and an in-house interferon-γ release assay (IGRA) was performed. Expression of chemokine ligand 4 (CCL4), chemokine ligand 10 (CXCL10), chemokine ligand 11 (CXCL11), interferon alpha (IFNA), radical S-adenosyl methionine domain-containing 2 (RSAD2), ubiquitin-specific peptidase 18 (USP18), interferon-induced protein 44 (IFI44), interferon-induced protein 44 like (IFI44L), interferon-induced protein tetratricopeptide repeats 1(IFIT1), and interleukin 2 receptor subunit alpha (IL2RA) mRNA levels were assessed by qPCR before, during, and after INH treatment. Results. We observed significantly lower relative abundances of USP18, IFI44L, IFNA, and IL2RA transcripts in PBMC from IGRA-positive individuals compared to levels in IGRA-negative individuals before INH therapy. Also, relative abundance of CXCL11 was significantly lower in IGRA-positive than in IGRA-negative individuals before and after one month of INH therapy. However, the relative abundance of CCL4, CXCL10, and CXCL11 mRNA was significantly decreased and that of IL2RA and USP18 significantly increased after INH therapy, regardless of the IGRA result. Our results show that USP18, IFI44L, IFIT1, and IL2RA relative abundances increased significantly, meanwhile the relative abundance of CCL4, CXCL11, and IFNA decreased significantly after six months of INH therapy in TST-positive individuals. Conclusions. Changes in the profiles of USP18, IL2RA, IFNA, CCL4, and CXCL11 expressions during INH treatment in TST-positive individuals, regardless of IGRA status, are potential tools for monitoring latent tuberculosis treatment.
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Huang, Limin, Chaoquan Hu, Hui Cao, Xiaoliang Wu, Rongpin Wang, He Lu, Hong Li, and Hui Chen. "MicroRNA-29c Increases the Chemosensitivity of Pancreatic Cancer Cells by Inhibiting USP22 Mediated Autophagy." Cellular Physiology and Biochemistry 47, no. 2 (2018): 747–58. http://dx.doi.org/10.1159/000490027.
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Background/Aims: Pancreatic cancer (PC) is an aggressive malignancy with a poor survival rate. Despite advances in the treatment of PC, the efficacy of therapy is limited by the development of chemoresistance. Here, we examined the role of microRNA-29c (miR-29c) and the involvement of autophagy and apoptosis in the chemoresistance of PC cells in vivo and in vitro. Methods: We employed qRT-PCR, western blot and immunofluorescence to examine the expression level of miR-29c, USP22 and autophagy relative protein. In addition, we used MTT assay to detect cell proliferation and transwell assay to measure migration and invasiveness. The apoptosis was determined using annexin V-FITC/PI apoptosis detection kit by flow cytometry. Luciferase reporter assays confirmed the relationship between USP22 and miR-29c. Results: miR-29c overexpression in the PC cell line PANC-1 enhanced the effect of gemcitabine on decreasing cell viability and inducing apoptosis and inhibited autophagy, as shown by western blotting, immunofluorescence staining, colony formation assays, and flow cytometry. Ubiquitin specific peptidase (USP)-22, a deubiquitinating enzyme known to induce autophagy and promote PC cell survival, was identified as a direct target of miR-29c. USP22 knockdown experiments indicated that USP22 suppresses gemcitabine-induced apoptosis by promoting autophagy, thereby increasing the chemoresistance of PC cells. Luciferase reporter assays confirmed that USP22 is a direct target of miR-29c. A xenograft mouse model demonstrated that miR-29c increases the chemosensitivity of PC in vivo by downregulating USP22, leading to the inhibition of autophagy and induction of apoptosis. Conclusions: Taken together, these findings reveal a potential mechanism underlying the chemoresistance of PC cells mediated by the regulation of USP22-mediated autophagy by miR-29c, suggesting potential targets and therapeutic strategies in PC.
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Agarwal, Srishti, Priyanka Mishra, Gururaj Shivange, Naveena Kodipelli, María Moros, Jesús M. de la Fuente, and Roy Anindya. "Citrate-capped gold nanoparticles for the label-free detection of ubiquitin C-terminal hydrolase-1." Analyst 140, no. 4 (2015): 1166–73. http://dx.doi.org/10.1039/c4an01935k.
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Lamback, Elisa Baranski, Carlos Henrique de Azeredo Lima, Renan Lyra Miranda, Alexandro Guterres, Felipe Andreiuolo, Luiz Eduardo Armondi Wildemberg, and Monica Roberto Gadelha. "USP8 Somatic Mutations in Cushing’s Disease and Silent Corticotropinomas." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A651. http://dx.doi.org/10.1210/jendso/bvab048.1328.
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Abstract Background: Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene have been described in Cushing’s disease (CD). These mutations increase proopiomelanocortin transcription resulting in ACTH production and seem to correlate with somatostatin receptor type 5 (SST5) expression. Aims: Screen USP8 in patients with corticotropinomas and correlate USP8 mutational status with SST5 expression in CD. Methods: Tumor DNA was extracted and then exon 14 amplified by PCR. SST5 was assessed by immunohistochemistry (clone UMB4) and quantified multiplying the percentage of positive cells (0,0%; <10%,1;10-50%, 2; 51-80%, 3; >80%, 4) and intensity (mild, 1; moderate, 2; intense, 3), giving a score (IRS) from 0-12 with ≥ 6 considered high. Results: Among 59 patients, 38 had CD and 21 silent corticotropinomas. In CD, 13 (34.2%) patients had pathogenic mutations (6 had p.Ser719del; 5 had p.Pro720Arg and 2 had p.Pro720Gln). In the mutated CD group, all were women and had median age of 34.5 years (20-46). Median ACTH was 64.7pg/mL [(34.8-330.0), normal <46], urinary free cortisol (UFC) 435.0μg/24h [(87.0-1386.0), normal <100], cortisol after overnight 1mg dexamethasone suppression test (ODST) 17.4μg/dL [(5.0-48.7), normal <1.8], salivary cortisol (SC) 8.1μg/dL [(1.0-15.5), normal <0.35]. Median largest tumor size was 0.9 cm (0-1.9), ki-67 1.7 (0.2-10.0) and IRS 12 (1-12). In wild-type CD group, 19 (76.0%) were women and had median age was 35.0 years old (14-62). Median ACTH was 59.7 (39.0-137.0), UFC 305.8 (77.0-1302.0), cortisol after ODST 23.6 (10.0-33.3), SC 0.67 (0.27-1.28). Median largest tumor diameter 0.7cm (0-3.3), ki-67 1.8 (0.2-10) and IRS 4 (0-12). SC was higher in mutated group compared to wild-type (p=0.001) as well as IRS (p=0.009). In silent corticotropinomas, 2 (9.5%) had pathogenic mutations (1 p.Ser718Pro and 1 p.Pro720Arg): male, 36 years old, 3.2 cm tumor, Ki-67 4%, IRS 6; and female, 52 years old, 3.4 cm tumor, Ki-67 2.5%, IRS 12, respectively. One tumor had a variant not reported as pathogenic (p.Thr739Ala): male, 46 years old, 3.7 cm tumor, Ki-67 0.5%, IRS 0. USP8-wild-type silent corticotropinomas had IRS 0-2. Conclusion: One third of CD patients presented with somatic USP8 mutation. Similar to another study, about 10% of silent corticotropinomas also presented somatic USP8 mutation. Expression of SST5 was high in USP8-mutated CD and higher than wild-type group.
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Zhu, Shaochun, Anna Wuolikainen, Junfang Wu, Anders Öhman, Gunnar Wingsle, Thomas Moritz, Peter M. Andersen, Lars Forsgren, and Miles Trupp. "Targeted Multiple Reaction Monitoring Analysis of CSF Identifies UCHL1 and GPNMB as Candidate Biomarkers for ALS." Journal of Molecular Neuroscience 69, no. 4 (November 12, 2019): 643–57. http://dx.doi.org/10.1007/s12031-019-01411-y.
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Abstract The neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD) share some common molecular deficits including disruption of protein homeostasis leading to disease-specific protein aggregation. While insoluble protein aggregates are the defining pathological confirmation of diagnosis, patient stratification based on early molecular etiologies may identify distinct subgroups within a clinical diagnosis that would respond differently in therapeutic development programs. We are developing targeted multiple reaction monitoring (MRM) mass spectrometry methods to rigorously quantify CSF proteins from known disease genes involved in lysosomal, ubiquitin-proteasomal, and autophagy pathways. Analysis of CSF from 21 PD, 21 ALS, and 25 control patients, rigorously matched for gender, age, and age of sample, revealed significant changes in peptide levels between PD, ALS, and control. In patients with PD, levels of two peptides for chromogranin B (CHGB, secretogranin 1) were significantly reduced. In CSF of patients with ALS, levels of two peptides from ubiquitin carboxy-terminal hydrolase like protein 1 (UCHL1) and one peptide each for glycoprotein non-metastatic melanoma protein B (GPNMB) and cathepsin D (CTSD) were all increased. Analysis of patients with ALS separated into two groups based on length of survival after CSF sampling revealed that the increases in GPNMB and UCHL1 were specific for short-lived ALS patients. While analysis of additional cohorts is required to validate these candidate biomarkers, this study suggests methods for stratification of ALS patients for clinical trials and identifies targets for drug efficacy measurements during therapeutic development.
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Funato, Kotaro, Naznin Haq, Yezhou Sun, Jin Chen, Greg Khitrov, Weijia Zhang, and David W. Sternberg. "Translational Regulation of Gene Expression by Cytoplasmic Nucleophosmin in AML: A Global Evaluation of RNA’s Differentially Recruited to Polyribosomes." Blood 110, no. 11 (November 16, 2007): 720. http://dx.doi.org/10.1182/blood.v110.11.720.720.
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Abstract Nucleophosmin (NPM) exon 12 mutations are found in 50–60 percent of acute myelogenous leukemia (AML) with normal karyotype, and the altered protein (termed NPMc) is relocalized from the nucleolus to the cytoplasm. Multiple functions have been attributed to NPM, and research by other investigators demonstrated that NPM serves a critical role in nucleolar-to-cytoplasmic shuttling of rRNA’s and in ribosome biogenesis. An early indication of the role of NPM in hematopoietic neoplasia was its fusion to the ALK protein in patients with anaplastic large cell lymphoma (ALCL). We and others have demonstrated that the expression of NPM-ALK regulates mediators of translational initiation, including mTOR, S6K1, and 4E-BP1, and we showed that NPM-ALK expression significantly alters the partitioning of mRNA’s to polyribosomes. Regulators of translational initiation can be rate-limiting for neoplasia in animal models, and we hypothesized that NPMc promotes leukemogenesis in a similar manner by altering the recruitment of specific mRNA’s to polysomes and thereby altering their translation. To evaluate this hypothesis, we assessed the global profile of polysomal mRNA in cells engineered to express NPMc. We generated pTRE2-NPMc(A)-Ba/F3 murine hematopoietic cells which express NPMc under the control of a tetracycline-inducible promoter. These cells carry “variant A” NPMc, which contains an insertion of a TCTG tetranucleotide at positions 956 through 959 and is the most common NPMc variant in AML. Control cells contained the empty vector. We used these cell lines to compare in a global manner the partitioning of mRNA species to polysomes, which were isolated using sucrose gradient fractionation of post-nuclear supernatants. From this enriched polysomal material we purified RNA, and the global profile of mRNA in these fractions was assessed by using Affymetrix mouse genome microarrays. The data generated in this effort was analyzed using the GeneChip robust multichip analysis (GCRMA) method. Significance Analysis of Microarrays (SAM) and Linear Models for Microarray Data (Limma) were employed to identify significant differentially expressed genes. We identified 345 genes whose mRNA’s exhibited altered polysomal partitioning, including 253 increased in cells with NPMc and 192 with decreased polysome association (FDR≤ 0.05). These translationally regulated mRNA’s encode proteins that control transcription, post-translational modification of proteins, and proteins associated with hematopoietic neoplasia. One of these differentially recruited mRNA’s encodes the Dub-1 protein, a ubiquitin peptidase that has been implicated previously in hematopoietic cell growth control, and the mRNA showed a 6-fold increase in polysome recruitment. Interestingly, in our previous evaluation comparing cells with NPM-ALK versus the kinase-deficient variant, there was a 50-fold increase in the partitioning of Dub-1 mRNA to polysomes. These findings suggest that alteration of Dub-1 expression through mRNA partitioning might be commonly utilized by both NPMc as well as NPM-ALK. Collectively, these findings suggest that concerted disruption of gene transcription and translation might broadly mediate the pathogenesis of hemotopoietic neoplasia.
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Pimentel, Agustin, Andrea O'Hara, Rosangela de Lima, Suying Xu, Ngoc Toomey, Carlos Brites, Yao-Shan Fan, and Juan Carlos Ramos. "Distinct Patterns of Genomic Alterations in Adult T-Cell Leukemia-Lymphoma Endemic in the Western World." Blood 124, no. 21 (December 6, 2014): 1698. http://dx.doi.org/10.1182/blood.v124.21.1698.1698.
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Abstract Introduction: Acute T-cell leukemia/lymphoma (ATLL) is a highly aggressive malignancy caused by HTLV-I, which is endemic in Japan, the Caribbean, and South America. ATLL carries a dismal prognosis and is generally incurable with conventional chemotherapy. ATLL is challenging to study at the molecular level, in part due to its complex genetic alterations likely resulting from years of HTLV-I driven T-cell proliferation and accumulation of genetic damage prior to malignant transformation. While no specific chromosome or genetic abnormalities have been proven to contribute to the pathogenesis of ATLL, older comparative genomic hybridization (CGH) studies performed in Japanese patients have demonstrated frequent genetic lesions (gains and losses) involving specific chromosomal regions, thus limited information exists about the chromosomal abnormalities occurring in the African ATLL variant commonly seen in the Western World. Methods: In this study, we used a high-density oligo array 244K platform CGH platform (Agilent Technologies) with an average resolution of 8.9 Kb, to perform a comprehensive genomic analysis of 47 ATLL patient tumor specimens obtained from African-descendants in the United States, Caribbean and Brazil. Patients were sub-classified as acute-type (A) ATLL (n=31), lymphomatous (L) (n=8), chronic (n=7, six whom had unfavorable features), and one with smouldering type according to Shimoyama criteria. DNA samples were extracted from peripheral blood mononuclear cells or tumor samples from these patients and checked for quality. Results: ATLL tumors exhibited complex genomic abnormalities and high copy number changes (CNCs). The average of copy number (CN) aberrations per sample was 238 in the L-group vs. 114 in acute/unfavorable chronic (A/UC) group. However, many chromosomal alterations were observed in this cohort, which had not been previously reported by other studies. The common CNCs were gains at 1q21-q44, 3, 3p, 7q22-q36, 8, 18, 19p13.1-p13.3, 21q21.1-q22.3, 22q12-q13 and losses at 5q13.2-q32, 6q11-q15, 9q13-q21. Gains in the 14 q32 (IGH) regions and losses in the 7p14.1 (TCRG), 7q34 (TCRB) and 14q11.2 (TCRA) regions involving small DNA segments were frequently observed. Genomic losses involving at least one or more known or candidate tumor suppressor genes were found in nearly all tumors, including some genes not previously implicated in ATLL. Some of the most significant gene or locus specific losses occurring in at least 20 % of the tumors in aggressive ATLL subtypes (A/UC and L) are summarized in Table 1. Losses of CDKN2A and CDKN2B tumor suppressor genes have been previously implicated in ATLL and other cancers. Several other genes found by this analysis have been implicated in apoptosis or cancer (i.e. CBLB, ANKRD11, IKZF1, and EPC1). IMMP2L deletion was associated with shorter survival time (2.3 weeks) compared with those cases without this gene deletion (29 weeks) in the A/UC group (p=0.005). ANKRD11 homo- or heterozygous deletions were seen in 37% of L-type and 19% of acute-type cases, and were associated with a shorter survival (13 vs. 43 weeks, p=<0.05) in the A group. CPN2/LRRC15 locus gains in 32% of A-type were linked to poorer survival (16 vs. 42 weeks, p=0.05). Table 1. GENE FUNCTION LOSSES (n) GAINS (n) NRXN3 Membrane receptor, cell adhesion 23 A/UC 3 L NS IMMP2L Mitochondrial inner membrane peptidase 16 A/UC* 5 L 4 A/UC CDKN2A/ CDKN2B (P16INK4/p15INK4b) Cyclin-dependent kinase inhibitors, tumor suppressors 16 A/UC 2 L 1 A/UC 1 L CBLB E3 ubiquitin protein ligase 12 A/UC 1 L NS ANKRD11 Transcriptional inhibitor, co-activator of p53 6 A/UC* 3 L NS CPN2 Carboxypeptidase NS 10 A/UC* 2 L IKZF1 Zinc-finger DNA binding proteins , lymphocyte differentiation NS 6 A/UC 3 L INSIG1 Endoplasmic reticulum membrane protein, intracellular lipid metabolism NS 10 A/UC 1 L EPC1 Member of the polycomb group family, transcriptional activator and repressor 10 A/UC 2 L NS * are genomic imbalances associated with a statistically significant reduction in survival. NS: non-significant. Conclusion: In sum, using a high resolution CGH array we observed distinct patterns ofgenetic aberrations in ATLL endemic in the Western World. We have successfully narrowed the genomic regions containing potential candidate genes that could be relevant to the pathogenesis of this fatal disease. Functional studies are required to determine the role of some of these genes in the pathogenesis of ATLL. Disclosures O'Hara: BioDiscovery, Inc.: Employment.
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Stachorski, Lena, Veera Raghavan Thangapandi, Dirk Reinhardt, and Jan-Henning Klusmann. "Characterization Of Oncogenes On Chromosome 21 Identified By shRNA-Based Viability Screening." Blood 122, no. 21 (November 15, 2013): 1201. http://dx.doi.org/10.1182/blood.v122.21.1201.1201.
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Abstract Children with trisomy 21 (Down syndrome, DS) are predisposed to develop acute megakaryoblastic leukemia (DS-AMKL) as well as the antecedent transient leukemia (DS-TL). Mutations in the hematopoietic transcription factor GATA1 have been found in nearly all children with DS-AMKL and DS-TL, but not in other malignancies. Recent whole genome sequencing efforts strongly supported the hypothesis that the triad of fetal origin, trisomy 21 and GATA1s-mutation are sufficient to cause DS-TL. Thus, the presence of an extra copy of hsa21 perturbs fetal hematopoiesis to provide a GATA1s sensitive background during leukemogenesis. To decipher the deregulated oncogenic gene network on hsa21, we conducted a shRNA-based viability screening. GATA1s-mutated DS-AMKL cell line CMK as well as non-DS-AML cell lines (K562, M-07) as control were lentivirally transduced and the effect of the knock-down was evaluated by cell viability and proliferation assays. Upon knock-down we found 42 genes conferring a profound selective growth disadvantage in DS-AMKL cell lines. Interestingly, 31 out of those candidate genes are located in one particular chromosomal region (21q22.1-21q22.3) and in addition 11 (out of 14 tested) are overexpressed in DS-AMKL compared to non-DS-AMKL. In a secondary functional validation screening the effects of the knock-down on the cell lines were analyzed by competition assays, apoptosis assays and cell viability assays as well as colony forming assays. Furthermore, differentiation and morphology were characterized using immunophenotyping and cytospins, respectively. We could demonstrate that the potential oncogenes participate in different cellular processes affecting proliferation, cell viability, apoptosis or differentiation. To further delineate the impact of 11 selected candidates on normal hematopoiesis, we characterized their effects in gain- and loss-of-function studies (confirmed by qRT-PCR) using CD34+ hematopoietic stem and progenitor cells (HSPCs). Four of those genes (USP25 [ubiquitin specific peptidase 25], BACH1 [BTB and CNC homology 1, basic leucine zipper transcription factor 1], U2AF1 [U2 small nuclear RNA auxiliary factor 1] and C21orf33) inhibited megakaryocytic and erythroid in vitro differentiation upon knockdown. The fraction of cells expressing early and late megakaryocytic markers CD41 and CD42b or early erythroid marker CD36 was reduced by 2-20-fold (P<0.001). Inversely, the knock-down of those four genes and two other genes (ATP5O [ATP synthase, H+ transporting, mitochondrial F1 complex, O subunit] and C21orf45) enhanced the myeloid differentiation propensity of CD34+-HSPCs (2.1-13.4-fold increase of CD14+-monocytic cells, P<0.001). The opposite effect was observed in gain-of-function studies. Ectopic expression of six genes (hU2AF1, mC21orf33, hIFNGR2 [interferon gamma receptor 2], hWDR4 [WD repeat domain 4] or mGABPA [GA binding protein transcription factor, alpha subunit 60kDa]) resulted in a radical switch in lineage commitment with a drastic change from erythroid to megakaryocytic differentiation (CD41+ 1.7-2.4-fold increase, P<0.001, CD235a+ [late erythroid marker] 3-300-fold reduction, P<0.001). Thus, we found a remarkable number of genes regulating erythroid and megakaryocytic differentiation as well as proliferation in normal hematopoiesis. Given the genetic background during trisomy 21-mediated leukemogenesis, we propose a complex interactive network located in one particular region on hsa21. Deregulation of this network might result in synergistic effects on hematopoietic differentiation, which promotes transformation of GATA1s-mutated fetal hematopoietic progenitor cells. Disclosures: No relevant conflicts of interest to declare.
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Shen, Lin Nan, Changjiang Dong, Huanting Liu, James H. Naismith, and Ronald T. Hay. "The structure of SENP1–SUMO-2 complex suggests a structural basis for discrimination between SUMO paralogues during processing." Biochemical Journal 397, no. 2 (June 28, 2006): 279–88. http://dx.doi.org/10.1042/bj20052030.
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The SUMO (small ubiquitin-like modifier)-specific protease SENP1 (sentrin-specific protease 1) can process the three forms of SUMO to their mature forms and deconjugate SUMO from modified substrates. It has been demonstrated previously that SENP1 processed SUMO-1 more efficiently than SUMO-2, but displayed little difference in its ability to deconjugate the different SUMO paralogues from modified substrates. To determine the basis for this substrate specificity, we have determined the crystal structure of SENP1 in isolation and in a transition-state complex with SUMO-2. The interface between SUMO-2 and SENP1 has a relatively poor complementarity, and most of the recognition is determined by interaction between the conserved C-terminus of SUMO-2 and the cleft in the protease. Although SENP1 is rather similar in structure to the related protease SENP2, these proteases have different SUMO-processing activities. Electrostatic analysis of SENP1 in the region where the C-terminal peptide, removed during maturation, would project indicates that it is the electrostatic complementarity between this region of SENP1 and the C-terminal peptides of the various SUMO paralogues that mediates selectivity.