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1
Bialik, Piotr, and Katarzyna Woźniak. "SUMO proteases as potential targets for cancer therapy." Postępy Higieny i Medycyny Doświadczalnej 71 (December 8, 2017): 0. http://dx.doi.org/10.5604/01.3001.0010.6667.
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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. SENPs (sentrin/SUMO-specific proteases) catalyze the deconjugation of SUMO proteins using their isopeptidase activity. These enzymes participate through hydrolase activity in the reaction of SUMO protein maturation, which involves the removal of a short fragment on the C-terminus of SUMO inactive form and exposure two glycine residues. SENPs are important for maintaining the balance between sumoylated and desumoylated proteins required for normal cellular physiology. Six SENP isoforms (SENP1, SENP2, SENP3, SENP5, SENP6 and SENP7) have been identified in mammals. These SENPs can be divided into three subfamilies based on their sequence homology, substrate specificity and subcellular localization. Results of studies indicate the role of SUMO proteases in the development of human diseases including cancer, suggesting that these proteins may be attractive targets for new drugs.
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Colnaghi, Luca, Andrea Conz, Luca Russo, Clara A. Musi, Luana Fioriti, Tiziana Borsello, and Mario Salmona. "Neuronal Localization of SENP Proteins with Super Resolution Microscopy." Brain Sciences 10, no. 11 (October 25, 2020): 778. http://dx.doi.org/10.3390/brainsci10110778.
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SUMOylation of proteins plays a key role in modulating neuronal function. For this reason, the balance between protein SUMOylation and deSUMOylation requires fine regulation to guarantee the homeostasis of neural tissue. While extensive research has been carried out on the localization and function of small ubiquitin-related modifier (SUMO) variants in neurons, less attention has been paid to the SUMO-specific isopeptidases that constitute the human SUMO-specific isopeptidase (SENP)/Ubiquitin-Specific Protease (ULP) cysteine protease family (SENP1-3 and SENP5-7). Here, for the first time, we studied the localization of SENP1, SENP6, and SENP7 in cultured hippocampal primary neurons at a super resolution detail level, with structured illumination microscopy (SIM). We found that the deSUMOylases partially colocalize with pre- and post-synaptic markers such as synaptophysin and drebrin. Thus, further confirming the presence with synaptic markers of the negative regulators of the SUMOylation machinery.
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Mohtashemipour, Hamzeh, Takavar Mohammadian, Mansour Torfi Mozanzadeh, Mehrzad Mesbah, and Abdolhossein Jangaran Nejad. "Dietary Selenium Nanoparticles Improved Growth and Health Indices in Asian Seabass (Lates calcarifer) Juveniles Reared in High Saline Water." Aquaculture Nutrition 2024 (January 10, 2024): 1–13. http://dx.doi.org/10.1155/2024/7480824.
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A 60-day study was carried out to determine the effect of dietary selenium nanoparticles (SeNP) on growth, digestive enzymes, and health status of Asian seabass (Lates calcarifer, 46.5 ± 0.2 g) juveniles reared in high saline water (48 ppt). Five levels of SeNP were added to a basal diet (45% protein, 15% lipid), including control (0), 0.5 (SeNP0.5), 1.0 (SeNP1), 2 (SeNP2), and 4 (SeNP4) mg SeNP kg−1 diet. Fish were stocked into fifteen 2,000 L tanks (50 fish tank−1) filled with 1,800 L sand-filtered seawater (26.5 ± 1.5°C, 48.0 ± 0.2 ppt) in a flow-through system. Each dietary treatment was performed in three replicates. The growth rate positively increased in both linear and quadratic trends with increasing dietary SeNP level (P<0.05). The liver Se concentration increased with increasing SeNP in diet (P<0.05). Gut total protease, trypsin, chymotrypsin, alkaline phosphatase (ALP), lipase, and α-amylase activities were significantly enhanced in the SeNP4 group compared to the other treatments (P<0.05). Antioxidant capacity improved in fish-fed SeNP2 and SeNP4 diets regarding catalase and superoxide dismutase activities and the liver glutathione content. Serum lysozyme and hemolytic activities and white blood cells’ respiratory burst activity in the control were lower than in fish-fed SeNP-supplemented diets. Serum total protein, globulin, and globulin/albumin ratio in fish-fed SeNP1, SeNP2, and SeNP4 diets were higher than the other groups (P<0.05). The interleukin-10 and granulocyte-macrophage colony-stimulating factor genes’ relative transcription levels in the gut of fish-fed SeNP4 were higher than the other groups. Serum cholesterol, triglycerides, ALP, aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase significantly decreased in fish with increasing SeNP content in the diet. In conclusion, supplementing the diet with 4 mg kg−1, SeNP was recommended to improve growth and health indices in L. calcarifer juveniles reared in high saline water (48 ppt).
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Xiang, Jia-Wen, Yuan Xiao, Yuwen Gan, Huimin Chen, Yunfei Liu, Ling Wang, Qian Nie, et al. "Glucose Oxidase- and UVA-Induced Changes in the Expression Patterns of Seven De-sumoylation Enzymes (SENPs) Are Associated with Cataract Development." Current Molecular Medicine 19, no. 1 (April 16, 2019): 48–53. http://dx.doi.org/10.2174/1566524019666190311094313.
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Objective: It has been well established that sumoylation acts as an important regulatory mechanism that controls many different cellular processes. We and others have shown that sumoylation plays an indispensable role during mouse eye development. Whether sumoylation is implicated in ocular pathogenesis remains to be further studied. In the present study, we have examined the expression patterns of the de-sumoylation enzymes (SENPs) in the in vitro cataract models induced by glucose oxidase and UVA irradiation. Methods: Four-week-old C57BL/6J mice were used in our experiments. Lenses were carefully dissected out from mouse eyes and cultured in M199 medium for 12 hours. Transparent lenses (without surgical damage) were selected for experimentation. The lenses were exposed to UVA for 60 min or treated with 20 mU/mL glucose oxidase (GO) to induce cataract formation. The mRNA levels were analyzed with qRT-PCR. The protein levels were determined with western blot analysis and quantitated with Image J. Results: GO treatment and UVA irradiation can induce cataract formation in lens cultured in vitro. GO treatment significantly down-regulated the mRNA levels for SENPs from 50% to 85%; on the other hand, expression of seven SENP proteins under GO treatment appeared in 3 situations: upregulation for SENP1, 2 and 6; downregulation for SENP 5 and 8; and unchanged for SENP3 and 7. UVA irradiation upregulates the mRNAs for all seven SENPs; In contrast to the mRNA levels for 7 SENPs, the expression levels for 6 SENPs (SENP1-3, 5-6 and 8) appeared down-regulated from 10% to 50%, and only SENP7 was slightly upregulated. Conclusion: Our results for the first time established the differentiation expression patterns of 7 de-sumoylation enzymes (SENPs) under treatment by GO or UVA, which provide preliminary data to link sumoylation to stress-induced cataractogenesis.
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Brand, Michael, Elias Benjamin Bommeli, Marc Rütimann, Urs Lindenmann, and Rainer Riedl. "Discovery of a Dual SENP1 and SENP2 Inhibitor." International Journal of Molecular Sciences 23, no. 20 (October 11, 2022): 12085. http://dx.doi.org/10.3390/ijms232012085.
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SUMOylation is a reversible post–translational modification (PTM) involving covalent attachment of small ubiquitin-related modifier (SUMO) proteins to substrate proteins. Dysregulation of SUMOylation and deSUMOylation results in cellular malfunction and is linked to various diseases, such as cancer. Sentrin-specific proteases (SENPs) were identified for the maturation of SUMOs and the deconjugation of SUMOs from their substrate proteins. Hence, this is a promising target tackling the dysregulation of the SUMOylation process. Herein, we report the discovery of a novel protein-protein interaction (PPI) inhibitor for SENP1-SUMO1 by virtual screening and subsequent medicinal chemistry optimization of the hit molecule. The optimized inhibitor ZHAWOC8697 showed IC50 values of 8.6 μM against SENP1 and 2.3 μM against SENP2. With a photo affinity probe the SENP target was validated. This novel SENP inhibitor represents a new valuable tool for the study of SUMOylation processes and the SENP-associated development of small molecule-based treatment options.
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Kolli, Nagamalleswari, Jowita Mikolajczyk, Marcin Drag, Debaditya Mukhopadhyay, Nela Moffatt, Mary Dasso, Guy Salvesen, and Keith D. Wilkinson. "Distribution and paralogue specificity of mammalian deSUMOylating enzymes." Biochemical Journal 430, no. 2 (August 13, 2010): 335–44. http://dx.doi.org/10.1042/bj20100504.
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The covalent attachment of SUMO (small ubiquitin-like protein modifier) to target proteins results in modifications in their activity, binding interactions, localization or half-life. The reversal of this modification is catalysed by SENPs (SUMO-specific processing proteases). Mammals contain four SUMO paralogues and six SENP enzymes. In the present paper, we describe a systematic analysis of human SENPs, integrating estimates of relative selectivity for SUMO1 and SUMO2, and kinetic measurements of recombinant C-terminal cSENPs (SENP catalytic domains). We first characterized the reaction of each endogenous SENP and cSENPs with HA–SUMO-VS [HA (haemagglutinin)-tagged SUMO-vinyl sulfones], active-site-directed irreversible inhibitors of SENPs. We found that all cSENPs and endogenous SENP1 react with both SUMO paralogues, whereas all other endogeneous SENPs in mammalian cells and tissues display high selectivity for SUMO2-VS. To obtain more quantitative data, the kinetic properties of purified cSENPs were determined using SUMO1- or SUMO2-AMC (7-amino-4-methylcoumarin) as substrate. All enzymes bind their respective substrates with high affinity. cSENP1 and cSENP2 process either SUMO substrate with similar affinity and catalytic efficiency; cSENP5 and cSENP6 show marked catalytic specificity for SUMO2 as measured by Km and kcat, whereas cSENP7 works only on SUMO2. Compared with cSENPs, recombinant full-length SENP1 and SENP2 show differences in SUMO selectivity, indicating that paralogue specificity is influenced by the presence of the variable N-terminal domain of each SENP. Our data suggest that SUMO2 metabolism is more dynamic than that of SUMO1 since most SENPs display a marked preference for SUMO2.
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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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Kaikkonen, Sanna, Tiina Jääskeläinen, Ulla Karvonen, Miia M. Rytinki, Harri Makkonen, Daniel Gioeli, Bryce M. Paschal, and Jorma J. Palvimo. "SUMO-Specific Protease 1 (SENP1) Reverses the Hormone-Augmented SUMOylation of Androgen Receptor and Modulates Gene Responses in Prostate Cancer Cells." Molecular Endocrinology 23, no. 3 (March 1, 2009): 292–307. http://dx.doi.org/10.1210/me.2008-0219.
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Abstract The acceptor sites for small ubiquitin-like modifier (SUMO) are conserved in the N-terminal domains of several nuclear receptors. Here, we show that androgens induce rapid and dynamic conjugation of SUMO-1 to androgen receptor (AR). Nuclear import of AR is not sufficient for SUMOylation, because constitutively nuclear apo-ARs or antagonist-bound ARs are only very weakly modified by SUMO-1 in comparison with agonist-bound ARs. Of the SUMO-specific proteases (SENP)-1, -2, -3, -5, and -6, only SENP1 and SENP2 are efficient in cleaving AR-SUMO-1 conjugates in intact cells and in vitro. Both SENP1 and -2 are nuclear and found at sites proximal to AR. Their expression promotes AR-dependent transcription, but in a promoter-selective fashion. SENP1 and -2 stimulated the activity of holo-AR on compound androgen response element-containing promoters. The effects of SENP1 and -2 on AR-dependent transcription were dependent on catalytic activity and required intact SUMO acceptor sites in AR, indicating that their coactivating effects are mainly due to their direct isopeptidase activity on holo-AR. In prostate cancer cells, ectopic expression of SENP1, but not that of SENP2, increased the transcription activity of endogenous AR. Silencing of SENP1 attenuated the expression of several AR target genes and blunted androgen-stimulated growth of LNCaP cells. Our results indicate that SENP1 reverses the ligand-induced SUMOylation of AR and helps fine tune the cellular responses to androgens in a target promoter-selective manner.
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Cubeñas-Potts, Caelin, Jacqueline D. Goeres, and Michael J. Matunis. "SENP1 and SENP2 affect spatial and temporal control of sumoylation in mitosis." Molecular Biology of the Cell 24, no. 22 (November 15, 2013): 3483–95. http://dx.doi.org/10.1091/mbc.e13-05-0230.
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Sumoylation of centromere, kinetochore, and other mitotic chromosome-associated proteins is essential for chromosome segregation. The mechanisms regulating spatial and temporal sumoylation of proteins in mitosis, however, are not well understood. Here we show that the small ubiquitin-related modifier (SUMO)–specific isopeptidases SENP1 and SENP2 are targeted to kinetochores in mitosis. SENP2 targeting occurs through a mechanism dependent on the Nup107-160 subcomplex of the nuclear pore complex and is modulated through interactions with karyopherin α. Overexpression of SENP2, but not other SUMO-specific isopeptidases, causes a defect in chromosome congression that depends on its precise kinetochore targeting. By altering SENP1 kinetochore associations, however, this effect on chromosome congression could be phenocopied. In contrast, RNA interference–mediated knockdown of SENP1 delays sister chromatid separation at metaphase, whereas SENP2 knockdown produces no detectable phenotypes. Our findings indicate that chromosome segregation depends on precise spatial and temporal control of sumoylation in mitosis and that SENP1 and SENP2 are important mediators of this control.
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Drag, Marcin, Jowita Mikolajczyk, I. M. Krishnakumar, Ziwei Huang, and Guy S. Salvesen. "Activity profiling of human deSUMOylating enzymes (SENPs) with synthetic substrates suggests an unexpected specificity of two newly characterized members of the family." Biochemical Journal 409, no. 2 (December 21, 2007): 461–69. http://dx.doi.org/10.1042/bj20070940.
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SENPs [Sentrin/SUMO (small ubiquitin-related modifier)-specific proteases] include proteases that activate the precursors of SUMOs, or deconjugate SUMOs attached to target proteins. SENPs are usually assayed on protein substrates, and for the first time we demonstrate that synthetic substrates can be convenient tools in determining activity and specificity of these proteases. We synthesized a group of short synthetic peptide fluorogenic molecules based on the cleavage site within SUMOs. We demonstrate the activity of human SENP1, 2, 5, 6, 7 and 8 on these substrates. A parallel positional scanning approach using a fluorogenic tetrapeptide library established preferences of SENPs in the P3 and P4 positions that allowed us to design optimal peptidyl reporter substrates. We show that the specificity of SENP1, 2, 5 and 8 on the optimal peptidyl substrates matches their natural protein substrates, and that the presence of the SUMO domain enhances catalysis by 2–3 orders of magnitude. We also show that SENP6 and 7 have an unexpected specificity that distinguishes them from other members of the family, implying that, in contrast to previous predictions, their natural substrate(s) may not be SUMO conjugates.
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Chow, Kin-Hoe, Suzanne Elgort, Mary Dasso, Maureen A. Powers, and Katharine S. Ullman. "The SUMO proteases SENP1 and SENP2 play a critical role in nucleoporin homeostasis and nuclear pore complex function." Molecular Biology of the Cell 25, no. 1 (January 2014): 160–68. http://dx.doi.org/10.1091/mbc.e13-05-0256.
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Nuclear pore complexes are composed of ∼30 different proteins, each present at the pore in multiple copies. Together these proteins create specialized channels that convey cargo between the cytoplasm and the nuclear interior. With the building blocks of nuclear pores identified, one challenge is to decipher how these proteins are coordinately produced and assembled into macromolecular pore structures with each cell division. Specific individual pore proteins and protein cofactors have been probed for their role in the assembly process, as well as certain kinases that add a layer of regulation via the phosphorylation status of nucleoporins. Other posttranslational modifications are candidates for coordinating events of pore assembly as well. In this study of two pore-associated small ubiquitin-like modifier (SUMO) proteases, sentrin/SUMO-specific protease 1 (SENP1) and SENP2, we observe that many nucleoporins are mislocalized and, in some cases, reduced in level when SENP1 and SENP2 are codepleted. The pore complexes present under these conditions are still capable of transport, although the kinetics of specific cargo is altered. These results reveal a new role for the pore-associated SENPs in nucleoporin homeostasis and in achieving proper configuration of the nuclear pore complex.
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Yun, Chawon, Yonggang Wang, Debaditya Mukhopadhyay, Peter Backlund, Nagamalleswari Kolli, Alfred Yergey, Keith D. Wilkinson, and Mary Dasso. "Nucleolar protein B23/nucleophosmin regulates the vertebrate SUMO pathway through SENP3 and SENP5 proteases." Journal of Cell Biology 183, no. 4 (November 17, 2008): 589–95. http://dx.doi.org/10.1083/jcb.200807185.
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Ubiquitin-like protein/sentrin-specific proteases (Ulp/SENPs) mediate both processing and deconjugation of small ubiquitin-like modifier proteins (SUMOs). Here, we show that Ulp/SENP family members SENP3 and SENP5 localize within the granular component of the nucleolus, a subnucleolar compartment that contains B23/nucleophosmin. B23/nucleophosmin is an abundant shuttling phosphoprotein, which plays important roles in ribosome biogenesis and which has been strongly implicated in hematopoietic malignancies. Moreover, we found that B23/nucleophosmin binds SENP3 and SENP5 in Xenopus laevis egg extracts and that it is essential for stable accumulation of SENP3 and SENP5 in mammalian tissue culture cells. After either codepletion of SENP3 and SENP5 or depletion of B23/nucleophosmin, we observed accumulation of SUMO proteins within nucleoli. Finally, depletion of these Ulp/SENPs causes defects in ribosome biogenesis reminiscent of phenotypes observed in the absence of B23/nucleophosmin. Together, these results suggest that regulation of SUMO deconjugation may be a major facet of B23/nucleophosmin function in vivo.
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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.
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Luo, Hua-Rong, Ying Liu, Xiao-Dong Wan, Jun-Liang Li, Min Wu, Qi-Min Zhang, Deng-Long Wu, Xin Zhao, and Tian-Ru Wang. "Sumoylation Negatively Regulates CSR1-Dependent Prostate Cancer Cell Death." Cellular Physiology and Biochemistry 46, no. 5 (2018): 1861–67. http://dx.doi.org/10.1159/000489370.
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Background/Aims: SUMOylation is a dynamic process and reversed by the activity of SUMO-specific proteases (SENPs) family. SENP1, a member of this family, is highly expressed and plays oncogenic roles in diverse cancers including prostate cancer. However, the SENP1-transgenic mice exhibit aberrant transformation of the mouse prostate gland but do not develop cancer. Cellular Stress Response 1 (CSR1) is a tumor suppressor gene and frequently deleted in prostate cancers. Overexpression of CSR1 in prostate cancer cells inhibits colony formation, anchorage-independent growth and induces cell death. Methods: The relationship between CSR1 and SENP1 were determined by immunoprecipitation-based proteomics screen and verified by GST-pull down assay. In vivo SUMOylation assay was used to detect the direct effect of SENP1 in the regulation of CSR1. Clustered regularly interspaced short palindromic repeats (CRISPR)–based gene editing was used to generate Senp1–/– and CSR1–/– PC3 cells. FACS assay was used to determine the apoptosis ratio of cells after transfection. Results: CSR1 is SUMOylated at K582 and rapid ubiquitinated and degradated in prostate cancer cells. SENP1 interacts with and deSUMOylates CSR1 to prevent its degradation and enhances CSR1-dependent prostate cancer cell death. Conclusion: Thus, our data indicates that CSR1 is a critical SUMOylated substrate of SENP1 that might partially explain the controversial roles of SENP1 in prostate cancer development.
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Hajmrle, Catherine, Mourad Ferdaoussi, Gregory Plummer, Aliya F. Spigelman, Krista Lai, Jocelyn E. Manning Fox, and Patrick E. MacDonald. "SUMOylation protects against IL-1β-induced apoptosis in INS-1 832/13 cells and human islets." American Journal of Physiology-Endocrinology and Metabolism 307, no. 8 (October 15, 2014): E664—E673. http://dx.doi.org/10.1152/ajpendo.00168.2014.
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Posttranslational modification by the small ubiquitin-like modifier (SUMO) peptides, known as SUMOylation, is reversed by the sentrin/SUMO-specific proteases (SENPs). While increased SUMOylation reduces β-cell exocytosis, insulin secretion, and responsiveness to GLP-1, the impact of SUMOylation on islet cell survival is unknown. Mouse islets, INS-1 832/13 cells, or human islets were transduced with adenoviruses to increase either SENP1 or SUMO1 or were transfected with siRNA duplexes to knockdown SENP1. We examined insulin secretion, intracellular Ca2+ responses, induction of endoplasmic reticulum stress markers and inducible nitric oxide synthase (iNOS) expression, and apoptosis by TUNEL and caspase 3 cleavage. Surprisingly, upregulation of SENP1 reduces insulin secretion and impairs intracellular Ca2+ handling. This secretory dysfunction is due to SENP1-induced cell death. Indeed, the detrimental effect of SENP1 on secretory function is diminished when two mediators of β-cell death, iNOS and NF-κB, are pharmacologically inhibited. Conversely, enhanced SUMOylation protects against IL-1β-induced cell death. This is associated with reduced iNOS expression, cleavage of caspase 3, and nuclear translocation of NF-κB. Taken together, these findings identify SUMO1 as a novel antiapoptotic protein in islets and demonstrate that reduced viability accounts for impaired islet function following SENP1 up-regulation.
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Xu, Zheng, So Fun Chau, Kwok Ho Lam, Ho Yin Chan, Tzi Bun Ng, and Shannon W. N. Au. "Crystal structure of the SENP1 mutant C603S–SUMO complex reveals the hydrolytic mechanism of SUMO-specific protease." Biochemical Journal 398, no. 3 (August 29, 2006): 345–52. http://dx.doi.org/10.1042/bj20060526.
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SUMO (small ubiquitin-related modifier)-specific proteases catalyse the maturation and de-conjugation processes of the sumoylation pathway and modulate various cellular responses including nuclear metabolism and cell cycle progression. The active-site cysteine residue is conserved among all known SUMO-specific proteases and is not substitutable by serine in the hydrolysis reactions demonstrated previously in yeast. We report here that the catalytic domain of human protease SENP1 (SUMO-specific protease 1) mutant SENP1CC603S carrying a mutation of cysteine to serine at the active site is inactive in maturation and de-conjugation reactions. To further understand the hydrolytic mechanism catalysed by SENP1, we have determined, at 2.8 Å resolution (1 Å=0.1 nm), the X-ray structure of SENP1CC603S–SUMO-1 complex. A comparison of the structure of SENP2–SUMO-1 suggests strongly that SUMO-specific proteases require a self-conformational change prior to cleavage of peptide or isopeptide bond in the maturation and de-conjugation processes respectively. Moreover, analysis of the interface of SENP1 and SUMO-1 has led to the identification of four unique amino acids in SENP1 that facilitate the binding of SUMO-1. By means of an in vitro assay, we further demonstrate a novel function of SENP1 in hydrolysing the thioester linkage in E1-SUMO and E2-SUMO complexes. The results disclose a new mechanism of regulation of the sumoylation pathway by the SUMO-specific proteases.
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Maruyama, Takuma, Yoichiro Abe, and Takako Niikura. "SENP1 and SENP2 regulate SUMOylation of amyloid precursor protein." Heliyon 4, no. 4 (April 2018): e00601. http://dx.doi.org/10.1016/j.heliyon.2018.e00601.
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G., Gayathri K., Puja Laxmanrao Shinde, Sebastian John, Sivakumar K. C., and Rashmi Mishra. "Understanding the Combined Effects of High Glucose Induced Hyper-Osmotic Stress and Oxygen Tension in the Progression of Tumourigenesis: From Mechanism to Anti-Cancer Therapeutics." Cells 12, no. 6 (March 7, 2023): 825. http://dx.doi.org/10.3390/cells12060825.
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High glucose (HG), a hallmark of the tumour microenvironment, is also a biomechanical stressor, as it exerts hyper-osmotic stress (HG-HO), but not much is known regarding how tumour cells mechanoadapt to HG-HO. Therefore, this study aimed to delineate the novel molecular mechanisms by which tumour cells mechanoadapt to HG/HG-HO and whether phytochemical-based interference in these mechanisms can generate tumour-cell-selective vulnerability to cell death. Mannitol and L-glucose were used as hyper-osmotic equivalents of high glucose. The results revealed that the tumour cells can efficiently mechanoadapt to HG-HO only in the normoxic microenvironment. Under normoxic HG/HG-HO stress, tumour cells polySUMOylate a higher pool of mitotic driver pH3(Ser10), which translocates to the nucleus and promotes faster cell divisions. On the contrary, acute hypoxia dampens HG/HG-HO-associated excessive proliferation by upregulating sentrin protease SENP7. SENP7 promotes abnormal SUMOylation of pH3(Ser10), thereby restricting its nuclear entry and promoting the M-phase arrest and cell loss. However, the hypoxia-arrested cells that managed to survive showed relapse upon reversal to normoxia as well as upregulation of pro-survival-associated SENP1, and players in tumour growth signalling, autophagy, glycolytic pathways etc. Depletion of SENP1 in both normoxia and hypoxia caused significant loss of tumour cells vs undepleted controls. SENP1 was ascertained to restrict the abnormal SUMOylation of pH3(Ser10) in both normoxia and hypoxia, although not so efficiently in hypoxia, due to the opposing activity of SENP7. Co-treatment with Momordin Ic (MC), a natural SENP1 inhibitor, and Gallic Acid (GA), an inhibitor of identified major pro-tumourigenic signalling (both enriched in Momordica charantia), eliminated surviving tumour cells in normal glucose, HG and HG-HO normoxic and hypoxic microenvironments, suggesting that appropriate and enhanced polySUMOylation of pH3(Ser10) in response to HG/HG-HO stress was attenuated by this treatment along with further dampening of other key tumourigenic signalling, due to which tumour cells could no longer proliferate and grow.
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XU, Zheng, and Shannon W. N. AU. "Mapping residues of SUMO precursors essential in differential maturation by SUMO-specific protease, SENP1." Biochemical Journal 386, no. 2 (February 22, 2005): 325–30. http://dx.doi.org/10.1042/bj20041210.
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SUMO (small ubiquitin-related modifier) is a member of the ubiquitin-like protein family that regulates cellular function of a variety of target proteins. SUMO proteins are expressed as their precursor forms. Cleavage of the residues after the ‘GG’ region of these precursors by SUMO-specific proteases in maturation is a prerequisite for subsequent sumoylation. To understand further this proteolytic processing, we expressed and purified SENP1 (sentrin-specific protease 1), one of the SUMO-specific proteases, using an Escherichia coli expression system. We show that SENP1 is capable of processing all SUMO-1, -2 and -3 in vitro; however, the proteolytic efficiency of SUMO-1 is the highest followed by SUMO-2 and -3. We demonstrate further that the catalytic domain of SENP1 (SENP1C) alone can determine the substrate specificity towards SUMO-1, -2 and -3. Replacement of the C-terminal fragments after the ‘GG’ region of SUMO-1 and -2 precursors with that of the SUMO-3, indicates that the C-terminal fragment is essential for efficient maturation. In mutagenesis analysis, we further map two residues immediately after the ‘GG’ region, which determine the differential maturation. Distinct patterns of tissue distribution of SENP1, SUMO-1, -2 and -3 are characterized. Taken together, we suggest that the observed differential maturation process has its physiological significance in the regulation of the sumoylation pathway.
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Pereira, Roberta Verciano, Fernanda Janku Cabral, Matheus de Souza Gomes, Liana Konovaloff Jannotti-Passos, William Castro-Borges, and Renata Guerra-Sá. "Transcriptional Profile and Structural Conservation of SUMO-Specific Proteases inSchistosoma mansoni." Journal of Parasitology Research 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/480824.
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Small ubiquitin-related modifier (SUMO) is involved in numerous cellular processes including protein localization, transcription, and cell cycle control. SUMOylation is a dynamic process, catalyzed by three SUMO-specific enzymes and reversed by Sentrin/SUMO-specific proteases (SENPs). Here we report the characterization of these proteases inSchistosoma mansoni. Usingin silicoanalysis, we identified two SENPs sequences, orthologs of mammalian SENP1 and SENP7, confirming their identities and conservation through phylogenetic analysis. In addition, the transcript levels ofSmsenp1/7in cercariae, adult worms, andin vitrocultivated schistosomula were measured by qRT-PCR. Our data revealed upregulation of theSmsenp1/7transcripts in cercariae and early schistosomula, followed by a marked differential gene expression in the other analyzed stages. However, no significant difference in expression profile between the paralogs was observed for the analyzed stages. Furthermore, in order to detect deSUMOylating capabilities in crude parasite extracts,SmSENP1 enzymatic activity was evaluated using SUMO-1-AMC substrate. The endopeptidase activity related to SUMO-1 precursor processing did not differ significantly between cercariae and adult worms. Taken together, these results support the developmentally regulated expression of SUMO-specific proteases inS. mansoni.
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Yu, Luyang, Weidong Ji, Haifeng Zhang, Matthew J. Renda, Yun He, Sharon Lin, Ee-chun Cheng, Hong Chen, Diane S. Krause, and Wang Min. "SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis." Journal of Experimental Medicine 207, no. 6 (May 10, 2010): 1183–95. http://dx.doi.org/10.1084/jem.20092215.
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Small ubiquitin-like modifier (SUMO) modification of proteins (SUMOylation) and deSUMOylation have emerged as important regulatory mechanisms for protein function. SENP1 (SUMO-specific protease) deconjugates SUMOs from modified proteins. We have created SENP1 knockout (KO) mice based on a Cre–loxP system. Global deletion of SENP1 (SENP1 KO) causes anemia and embryonic lethality between embryonic day 13.5 and postnatal day 1, correlating with erythropoiesis defects in the fetal liver. Bone marrow transplantation of SENP1 KO fetal liver cells to irradiated adult recipients confers erythropoiesis defects. Protein analyses show that the GATA1 and GATA1-dependent genes are down-regulated in fetal liver of SENP1 KO mice. This down-regulation correlates with accumulation of a SUMOylated form of GATA1. We further show that SENP1 can directly deSUMOylate GATA1, regulating GATA1-dependent gene expression and erythropoiesis by in vitro assays. Moreover, we demonstrate that GATA1 SUMOylation alters its DNA binding, reducing its recruitment to the GATA1-responsive gene promoter. Collectively, we conclude that SENP1 promotes GATA1 activation and subsequent erythropoiesis by deSUMOylating GATA1.
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Sun, Xiao-Xin, Yingxiao Chen, Yulong Su, Xiaoyan Wang, Krishna Mohan Chauhan, Juan Liang, Colin J. Daniel, Rosalie C. Sears, and Mu-Shui Dai. "SUMO protease SENP1 deSUMOylates and stabilizes c-Myc." Proceedings of the National Academy of Sciences 115, no. 43 (October 10, 2018): 10983–88. http://dx.doi.org/10.1073/pnas.1802932115.
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Posttranslational modifications play a crucial role in the proper control of c-Myc protein stability and activity. c-Myc can be modified by small ubiquitin-like modifier (SUMO). However, how SUMOylation regulates c-Myc stability and activity remains to be elucidated. The deSUMOylation enzyme, SENP1, has recently been shown to have a prooncogenic role in cancer; however, mechanistic understanding of this is limited. Here we show that SENP1 is a c-Myc deSUMOylating enzyme. SENP1 interacts with and deSUMOylates c-Myc in cells and in vitro. Overexpression of wild-type SENP1, but not its catalytically inactive C603S mutant, markedly stabilizes c-Myc and increases its levels and activity. Knockdown of SENP1 reduces c-Myc levels, induces cell cycle arrest, and drastically suppresses cell proliferation. We further show that c-Myc can be comodified by both ubiquitination and SUMOylation. SENP1-mediated deSUMOylation reduces c-Myc polyubiquitination, suggesting that SUMOylation promotes c-Myc degradation through the proteasome system. Interestingly, SENP1-mediated deSUMOylation promotes the accumulation of monoubiquitinated c-Myc and its phosphorylation at serine 62 and threonine 58. SENP1 is frequently overexpressed, correlating with the high expression of c-Myc, in breast cancer tissues. Together, these results reveal that SENP1 is a crucial c-Myc deSUMOylating enzyme that positively regulates c-Myc’s stability and activity.
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Liu, Yan, Yali Shen, Yang Song, Lei Xu, J. Jefferson P. P. Perry, and Jiayu Liao. "Isopeptidase Kinetics Determination by a Real Time and Sensitive qFRET Approach." Biomolecules 11, no. 5 (April 30, 2021): 673. http://dx.doi.org/10.3390/biom11050673.
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Isopeptidase activity of proteases plays critical roles in physiological and pathological processes in living organisms, such as protein stability in cancers and protein activity in infectious diseases. However, the kinetics of protease isopeptidase activity has not been explored before due to a lack of methodology. Here, we report the development of novel qFRET-based protease assay for characterizing the isopeptidase kinetics of SENP1. The reversible process of SUMOylation in vivo requires an enzymatic cascade that includes E1, E2, and E3 enzymes and Sentrin/SUMO-specific proteases (SENPs), which can act either as endopeptidases that process the pre-SUMO before its conjugation, or as isopeptidases to deconjugate SUMO from its target substrate. We first produced the isopeptidase substrate of CyPet-SUMO1/YPet-RanGAP1c by SUMOylation reaction in the presence of SUMO E1 and E2 enzymes. Then a qFRET analyses of real-time FRET signal reduction of the conjugated substrate of CyPet-SUMO1/YPet-RanGAP1c to free CyPet-SUMO1 and YPet-RanGAP1c by the SENP1 were able to obtain the kinetic parameters, Kcat, KM, and catalytic efficiency (Kcat/KM) of SENP1. This represents a pioneer effort in isopeptidase kinetics determination. Importantly, the general methodology of qFRET-based protease isopeptidase kinetic determination can also be applied to other proteases.
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Gao, Jian, Xia Chen, Qing Gu, Xiaoxiao Liu, and Xun Xu. "SENP1-Mediated Desumoylation of DBC1 Inhibits Apoptosis Induced by High Glucose in Bovine Retinal Pericytes." Journal of Ophthalmology 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/6392658.
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Pericyte loss is an early characteristic change in diabetic retinopathy, but its precise molecular mechanisms have not been elucidated. This study investigated the role of SENP1 in pericyte loss in diabetic retinopathy. We demonstrated that a high concentration of glucose inhibited the expression of the Sentrin/SUMO-specific protease 1 (SENP1), which resulted in an increase in DBC1 sumoylation in bovine retinal pericytes (BRPCs). Furthermore, SENP1 overexpression attenuated hyperemia-induced apoptosis of BPRCs, and SENP1 knockdown aggravated this effect. We also provide evidence that DBC1 sumoylation/desumoylation is involved in the SENP1-regulated apoptosis of BRPCs under high glucose conditions. Understanding the role of SENP1 in the pathogenesis of high glucose induced pericyte loss could help elucidate important targets for future pharmacological interventions.
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Mu, Juwei, Yong Zuo, Wenjing Yang, Zhaoli Chen, Ziyuan Liu, Jun Tu, Yan Li, Zuyang Yuan, Jinke Cheng, and Jie He. "Over-expression of small ubiquitin-like modifier proteases 1 predicts chemo-sensitivity and poor survival in non-small cell lung cancer." Chinese Medical Journal 127, no. 23 (December 5, 2014): 4060–65. http://dx.doi.org/10.3760/cma.j.issn.0366-6999.20141013.
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Background Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors. Despite the advances in therapy over the years, its mortality remains high. The aim of this study was to evaluate the expression of small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) in NSCLC tissues and its role in the regulation of vascular endothelial growth factor (VEGF) expression. We also investigated the association between the expression level of SENP1 and the clinicopathological features and survival of the patients. Methods A SENP1 small interfering RNA (siRNA) was constructed and transfected into the NSCLC cells. VEGF gene expression was analyzed by real-time polymerase chain reaction (RT-PCR). Immunohistochemistry staining was used to assess the expression of SENP1 in 100 NSCLC patients and its association with the clinicopathological features and survival was analyzed. Results VEGF expression was significantly higher in NSCLC tissues than in normal lung tissues. Inhibition of SENP1 by siRNA was associated with decreased VEGF expression. SENP1 was over-expressed in 55 of the 100 NSCLC samples (55%) and was associated with a moderate and low histological tumor grade (3.6%, 38.2%, and 58.2% in high, moderate and low differentiated tumors, respectively, P=0.046), higher T stage (10.9% in T1, and 89.1% in T2 and T3 tumor samples, P <0.001) and TNM stage (10.9% in stage I, and 89.1% in stages II and III tumor samples, P <0.001). The rate of lymph node metastasis was significantly higher in the SENP1 over-expression group (76.4%) than that in the SENP1 low expression group (33.3%, P <0.001). Sixty three patients received postoperative chemotherapy, including 34 with SENP1 over-expression and 29 with SENP1 low expression. Among the 34 patients with SENP1 over-expression, 22 (64.7%) patients developed recurrence or metastasis, significantly higher than those in the low expression group 27.6% (8/29) (P=0.005). Multivariate Cox regression analysis showed that lymph node metastasis (P=0.015), TNM stage (P=0.001), and SENP1 expression level (P=0.002) were independent prognostic factors for the survival of NSCLC patients. Conclusions SENP1 may be a promising predictor of survival, a predictive factor of chemo-sensitivity for NSCLC patients, and potentially a desirable drug target for lung carcinoma target therapy.
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Yu, Tingting, Yong Zuo, Rong Cai, Xian Huang, Shuai Wu, Chenxi Zhang, Y. Eugene Chin, et al. "SENP1 regulates IFN-γ−STAT1 signaling through STAT3−SOCS3 negative feedback loop." Journal of Molecular Cell Biology 9, no. 2 (October 26, 2016): 144–53. http://dx.doi.org/10.1093/jmcb/mjw042.
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Abstract Interferon-γ (IFN-γ) triggers macrophage for inflammation response by activating the intracellular JAK−STAT1 signaling. Suppressor of cytokine signaling 1 (SOCS1) and protein tyrosine phosphatases can negatively modulate IFN-γ signaling. Here, we identify a novel negative feedback loop mediated by STAT3−SOCS3, which is tightly controlled by SENP1 via de-SUMOylation of protein tyrosine phosphatase 1B (PTP1B), in IFN-γ signaling. SENP1-deficient macrophages show defects in IFN-γ signaling and M1 macrophage activation. PTP1B in SENP1-deficient macrophages is highly SUMOylated, which reduces PTP1B-induced de-phosphorylation of STAT3. Activated STAT3 then suppresses STAT1 activation via SOCS3 induction in SENP1-deficient macrophages. Accordingly, SENP1-deficient macrophages show reduced ability to resist Listeria monocytogenes infection. These results reveal a crucial role of SENP1-controlled STAT1 and STAT3 balance in macrophage polarization.
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Ji, Mingfei, Zongtao Chai, Jie Chen, Gang Li, Qiang Li, Miao Li, Yelei Ding, Shaoyong Lu, Guanqun Ju, and Jianquan Hou. "Insights into the Allosteric Effect of SENP1 Q597A Mutation on the Hydrolytic Reaction of SUMO1 via an Integrated Computational Study." Molecules 27, no. 13 (June 28, 2022): 4149. http://dx.doi.org/10.3390/molecules27134149.
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Small ubiquitin-related modifier (SUMO)-specific protease 1 (SENP1) is a cysteine protease that catalyzes the cleavage of the C-terminus of SUMO1 for the processing of SUMO precursors and deSUMOylation of target proteins. SENP1 is considered to be a promising target for the treatment of hepatocellular carcinoma (HCC) and prostate cancer. SENP1 Gln597 is located at the unstructured loop connecting the helices α4 to α5. The Q597A mutation of SENP1 allosterically disrupts the hydrolytic reaction of SUMO1 through an unknown mechanism. Here, extensive multiple replicates of microsecond molecular dynamics (MD) simulations, coupled with principal component analysis, dynamic cross-correlation analysis, community network analysis, and binding free energy calculations, were performed to elucidate the detailed mechanism. Our MD simulations showed that the Q597A mutation induced marked dynamic conformational changes in SENP1, especially in the unstructured loop connecting the helices α4 to α5 which the mutation site occupies. Moreover, the Q597A mutation caused conformational changes to catalytic Cys603 and His533 at the active site, which might impair the catalytic activity of SENP1 in processing SUMO1. Moreover, binding free energy calculations revealed that the Q597A mutation had a minor effect on the binding affinity of SUMO1 to SENP1. Together, these results may broaden our understanding of the allosteric modulation of the SENP1−SUMO1 complex.
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Vishwamitra, Deeksha, Choladda V. Curry, Serhan Alkan, Ping Shi, and Hesham M. Amin. "Sumoylation Sustains the Stability of NPM-ALK Oncogenic Protein and Facilitates Its Nuclear Accumulation in T-Cell Anaplastic Large-Cell Lymphoma." Blood 124, no. 21 (December 6, 2014): 3586. http://dx.doi.org/10.1182/blood.v124.21.3586.3586.
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Abstract Anaplastic lymphoma kinase-expressing anaplastic large-cell lymphoma (ALK+ ALCL) is an aggressive type of T-cell non-Hodgkin lymphoma. The expression of ALK in T-cell lymphoma is an aberrant event that results from one of several chromosomal abnormalities. The t(2;5)(p23;q35) chromosomal translocation constitutes 85% of these abnormalities, and leads to the fusion of the nucleophosmin (NPM) gene on 2p23 and the ALK gene on 5q35. This translocation induces the generation of NPM-ALKoncogene, which encodes the expression of NPM-ALK chimeric tyrosine kinase. NPM-ALK induces lymphomagenic effects through the formation of the constitutively activated NPM-ALK/NPM-ALK homodimers, which phosphorylate downstream survival-promoting proteins including JAK/STAT, PI3K/AKT, and MAP kinase. Although it resides in the cytoplasm, NPM-ALK is also capable of forming the wild-type ALK/NPM-ALK heterodimers that translocate to the nucleus. Notably, the mechanisms that promote the stability and mediate the translocation of NPM-ALK from the cytoplasm to the nucleus are not completely understood. SUMOylation is a post-translational modification that is characterized by the covalent and reversible binding of small ubiquitin-like modifiers (SUMO), including SUMO-1, SUMO-2/3, and SUMO-4, with their target proteins. Although SUMOylation has some similarities with ubiquitination, it has been shown that SUMO proteins compete with ubiquitin for substrate binding and thus SUMOylation protects target proteins from proteasomal degradation. In addition to enhancing protein stability, SUMO proteins are involved in nuclear translocation of target proteins, which affects processes essential for cellular homeostasis. SUMO family of proteins also includes the sentrin-specific proteases (SENPs): SENP1-3 and SENP5-7. The roles of SENPs encompass removal of SUMO from target proteins; thus suppressing protein stabilization induced by SUMOylation. It has been recently demonstrated that SUMOylation plays a key role in the progression of cancer. For instance, SUMOylation inhibits cancer development through stabilization of tumor suppressor genes or promote cancer development through stabilization of oncogenes. Because it is also involved in DNA damage repair mechanisms that ensure maintenance and stabilization of genomic integrity, it is thought that SUMOylation has the ability to promote tumor development and to initiate chemo-resistance in cancer cells. In this study, we hypothesized that defects in SUMOylation system exist in NPM-ALK+ T-cell lymphoma and contribute to the stabilization of NPM-ALK protein and its accumulation in the nucleus. Using the online software SUMOplot (http://www.abgent.com/sumoplot), we identified potential SUMO consensus binding sites within NPM-ALK amino acid sequence. Analyzing the expression levels of SUMO proteins by Western blotting demonstrated universal upregulation of the SUMO proteins and substantial decrease in the deSUMOylating protein SENP1 in 5 NPM-ALK+ T-cell lymphoma cell lines compared with normal human T lymphocytes. Furthermore, similar patterns of SUMO and SENP1 expressions were detected in 15 primary ALK+ T-cell lymphoma tumors from patients. Immunoprecipitation showed binding between the SUMO and NPM-ALK proteins. In vitro SUMOylation assays provided novel evidence that SUMO-1 and SUMO-3 induce SUMOylation of NPM-ALK at Lys24 and Lys32, and these findings were further confirmed using a protein degradation assay. In addition, transfection of the NPM-ALK+ T-cell lymphoma cells with a SENP1 expression plasmid decreased the expression levels of the SUMO and NPM-ALK proteins, and abrogated the accumulation of NPM-ALK in the nucleus. SENP1-induced effects were associated with decreased cell viability, proliferation, migration, and anchorage-independent colony formation of NPM-ALK+T-cell lymphoma cells. In summary, we identify for the first time defects in the SUMOylation system as novel mechanisms contributing to the pathogenesis of NPM-ALK+ T-cell lymphoma. Unraveling such mechanisms is expected to advance current understanding of the pathobiology of this lymphoma and may lead to devising novel strategies to eradicate this aggressive form of cancer. Disclosures No relevant conflicts of interest to declare.
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Huang, Binbin, Bing Xiu, and Aibin Liang. "Application of SENP-1, HIF-1α and VEGF Gene Expressions in Prognostic Prediction for Normal Karyotypic Acute Leukemia Patients with NPM1 + and FLT3-ITD-." Blood 114, no. 22 (November 20, 2009): 4723. http://dx.doi.org/10.1182/blood.v114.22.4723.4723.
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Abstract Abstract 4723 In our study, 26 BM species from 23 normal karyotypic acute leukemia patients (non-APL) with NPM+ and FLT3-ITD- gene mutation were collected in our department. Compared to healthy controls, SENP1, HIF-1alpha and VEGF mRNA expression in ALL and AML patients were elevated to 10.0, 13.2, 16.6 and 43.1, 97.75, 240.0 folds, respectively, by RT-real time PCR. The levels of SENP1, HIF-1αand VEGF mRNA in AML patients were greatly higher than those in ALL (p<0.05). SENP1 and HIF-1alpha expression levels were positively and significantly correlated (linear regression analysis, r = 0.88, p<0.05) both in ALL and AML. The correlation between HIF-1alpha and VEGF mRNA level was statistically significant (linear regression analysis, r = 0.34, p<0.05). Among AML patients, SENP1, HIF-1alpha and VEGF gene expressive level in non-response (NR) patients (n=7) were higher than patients with CR (n=9), p<0.01. For ALL patients, the expressive level (‘X±S) of SENP1, HIF-1alpha, VEGF gene in NR(n=3)were slightly higher than those in CR (n=4): 10.5±2.7, 6.8±3.4; 13.2±16.6, 3.9±3.0; 13.1±10.1,11.1±12.1. Elevated gene expression of SENP1, HIF-1alpha and VEGF indicate shorter survival time of patients, p<0.01.The levels of SENP1, HIF-1alpha and VEGF gene decreased after treatment in 3 AML patients. Thus, higher SENP1, HIF-1alpha and VEGF gene levels might be associated with shortened survival and worse clinical process. Therefore, although higher expression of SENP1, HIF-1alpha and VEGF gene might throw an impact on the prognostic prediction in acute leukemia patients, confirmation of this hypothesis need to be done in more large population. Disclosures: No relevant conflicts of interest to declare.
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Cui, Chun-Ping, Carmen Chak-Lui Wong, Alan Ka-Lun Kai, Daniel Wai-Hung Ho, Eunice Yuen-Ting Lau, Yu-Man Tsui, Lo-Kong Chan, et al. "SENP1 promotes hypoxia-induced cancer stemness by HIF-1α deSUMOylation and SENP1/HIF-1α positive feedback loop." Gut 66, no. 12 (March 3, 2017): 2149–59. http://dx.doi.org/10.1136/gutjnl-2016-313264.
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ObjectiveWe investigated the effect and mechanism of hypoxic microenvironment and hypoxia-inducible factors (HIFs) on hepatocellular carcinoma (HCC) cancer stemness.DesignHCC cancer stemness was analysed by self-renewal ability, chemoresistance, expression of stemness-related genes and cancer stem cell (CSC) marker-positive cell population. Specific small ubiquitin-like modifier (SUMO) proteases 1 (SENP1) mRNA level was examined with quantitative PCR in human paired HCCs. Immunoprecipitation was used to examine the binding of proteins and chromatin immunoprecipitation assay to detect the binding of HIFs with hypoxia response element sequence. In vivo characterisation was performed in immunocompromised mice and stem cell frequency was analysed.ResultsWe showed that hypoxia enhanced the stemness of HCC cells and hepatocarcinogenesis through enhancing HIF-1α deSUMOylation by SENP1 and increasing stabilisation and transcriptional activity of HIF-1α. Furthermore, we demonstrated that SENP1 is a direct target of HIF-1/2α and a previously unrecognised positive feedback loop exists between SENP1 and HIF-1α.ConclusionsTaken together, our findings suggest the significance of this positive feedback loop between HIF-1α and SENP1 in contributing to the increased cancer stemness in HCC and hepatocarcinogenesis under hypoxia. Drugs that specifically target SENP1 may offer a potential novel therapeutic approach for HCC.
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Cheng, Jinke, Dachun Wang, Zhengxin Wang, and Edward T. H. Yeh. "SENP1 Enhances Androgen Receptor-Dependent Transcription through Desumoylation of Histone Deacetylase 1." Molecular and Cellular Biology 24, no. 13 (July 1, 2004): 6021–28. http://dx.doi.org/10.1128/mcb.24.13.6021-6028.2004.
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ABSTRACT SUMO (also called Sentrin) is a ubiquitin-like protein that plays an important role in regulating protein function and localization. It is known that several nuclear receptors are modified by SUMO; however, the effect of desumoylation in regulating nuclear receptor function has not been elucidated. Here we show that androgen receptor (AR)-mediated transcription is markedly enhanced by SENP1, a member of SUMO-specific protease family. SENP1's ability to enhance AR-dependent transcription is not mediated through desumoylation of AR, but rather through its ability to deconjugate histone deacetylase 1 (HDAC1), thereby reducing its deacetylase activity. HDAC1's repressive effect on AR-dependent transcription could be reversed by SENP1 and by deletion of its sumoylation sites. RNA interference depletion of endogenous HDAC1 also reduced SENP1's effect. Thus, SENP1 could regulate AR-dependent transcription through desumoylation of HDAC1. These studies provide insights on the potential role of desumoylation in the regulation of nuclear receptor activity.
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Ambaye, Nigus D. "Noncovalent structure of SENP1 in complex with SUMO2." Acta Crystallographica Section F Structural Biology Communications 75, no. 5 (April 24, 2019): 332–39. http://dx.doi.org/10.1107/s2053230x19004266.
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SUMOylation is a post-translational modification in which a small ubiquitin-like molecule (SUMO) is appended to substrate proteins and is known to influence myriads of biological processes. A delicate interplay between several families of SUMOylation proteins and their substrates ensures the proper level of SUMOylation required for normal cell function. Among the SUMO proteins, SUMO2 is known to form mono-SUMOylated proteins and engage in poly-SUMO chain formation, while sentrin-specific protease 1 (SENP1) is a key enzyme in regulating both events. Determination of the SENP1–SUMO2 interaction is therefore necessary to better understand SUMOylation. In this regard, the current paper reports the noncovalent structure of SENP1 in complex with SUMO2, which was refined to a resolution of 2.62 Å withRandRfreevalues of 22.92% and 27.66%, respectively. The structure shows that SENP1–SUMO2 complex formation is driven largely by polar interactions and limited hydrophobic contacts. The essential C-terminal motif (QQTGG) of SUMO2 is stabilized by a number of specific bonding interactions that enable it to protrude into the catalytic triad of SENP1 and provide the arrangement necessary for maturation of SUMO and deSUMOylation activity. Overall, the structure shows a number of structural details that pinpoint the basis of SENP1–SUMO2 complex formation.
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Mirecka, Alicja, Zbigniew Morawiec, and Katarzyna Wozniak. "Genetic Polymorphism of SUMO-Specific Cysteine Proteases − SENP1 and SENP2 in Breast Cancer." Pathology & Oncology Research 22, no. 4 (May 13, 2016): 817–23. http://dx.doi.org/10.1007/s12253-016-0064-7.
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Alegre, Kamela O., and David Reverter. "Swapping Small Ubiquitin-like Modifier (SUMO) Isoform Specificity of SUMO Proteases SENP6 and SENP7." Journal of Biological Chemistry 286, no. 41 (August 30, 2011): 36142–51. http://dx.doi.org/10.1074/jbc.m111.268847.
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SUMO proteases can regulate the amounts of SUMO-conjugated proteins in the cell by cleaving off the isopeptidic bond between SUMO and the target protein. Of the six members that constitute the human SENP/ULP protease family, SENP6 and SENP7 are the most divergent members in their conserved catalytic domain. The SENP6 and SENP7 subclass displays a clear proteolytic cleavage preference for SUMO2/3 isoforms. To investigate the structural determinants for such isoform specificity, we have identified a unique sequence insertion in the SENP6 and SENP7 subclass that is essential for their proteolytic activity and that forms a more extensive interface with SUMO during the proteolytic reaction. Furthermore, we have identified a region in the SUMO surface determinant for the SUMO2/3 isoform specificity of SENP6 and SENP7. Double point amino acid mutagenesis on the SUMO surface allows us to swap the specificity of SENP6 and SENP7 between the two SUMO isoforms. Structure-based comparisons combined with biochemical and mutagenesis analysis have revealed Loop 1 insertion in SENP6 and SENP7 as a platform to discriminate between SUMO1 and SUMO2/3 isoforms in this subclass of the SUMO protease family.
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Yu, Lan, Xiyun Bian, Chunyan Zhang, Zhouying Wu, Na Huang, Jie Yang, Wen Jin, et al. "Ginkgolic acid improves bleomycin-induced pulmonary fibrosis by inhibiting SMAD4 SUMOylation." Oxidative Medicine and Cellular Longevity 2022 (June 6, 2022): 1–18. http://dx.doi.org/10.1155/2022/8002566.
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Idiopathic pulmonary fibrosis (IPF) is a refractory chronic respiratory disease with progressively exacerbating symptoms and a high mortality rate. There are currently only two effective drugs for IPF; thus, there is an urgent need to develop new therapeutics. Previous experiments have shown that ginkgolic acid (GA), as a SUMO-1 inhibitor, exerted an inhibitory effect on cardiac fibrosis induced by myocardial infarction. Regarding the pathogenesis of PF, previous studies have concluded that small ubiquitin-like modifier (SUMO) polypeptides bind multiple target proteins and participate in fibrosis of multiple organs, including PF. In this study, we found altered expression of SUMO family members in lung tissues from IPF patients. GA mediated the reduced expression of SUMO1/2/3 and the overexpression of SENP1 in a PF mouse model, which improved PF phenotypes. At the same time, the protective effect of GA on PF was also confirmed in the SENP1-KO transgenic mice model. Subsequent experiments showed that SUMOylation of SMAD4 was involved in PF. It was inhibited by TGF-β1, but GA could reverse the effects of TGF-β1. SENP1 also inhibited the SUMOylation of SMAD4 and then participated in epithelial-mesenchymal transition (EMT) downstream of TGF-β1. We also found that SENP1 regulation of SMAD4 SUMOylation affected reactive oxygen species (ROS) production during TGF-β1-induced EMT and that GA prevented this oxidative stress through SENP1. Therefore, GA may inhibit the SUMOylation of SMAD4 through SENP1 and participate in TGF-β1-mediated pulmonary EMT, all of which reduce the degree of PF. This study provided potential novel targets and a new alternative for the future clinical testing in PF.
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Chow, Kin-Hoe, Suzanne Elgort, Mary Dasso, and Katharine S. Ullman. "Two distinct sites in Nup153 mediate interaction with the SUMO proteases SENP1 and SENP2." Nucleus 3, no. 4 (July 2012): 349–58. http://dx.doi.org/10.4161/nucl.20822.
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Bailey, Daniel, and Peter O’Hare. "Herpes simplex virus 1 ICP0 co-localizes with a SUMO-specific protease." Journal of General Virology 83, no. 12 (December 1, 2002): 2951–64. http://dx.doi.org/10.1099/0022-1317-83-12-2951.
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Early during infection, the herpes simplex regulatory protein ICP0 promotes the proteasome-dependent degradation of a number of cellular proteins and the loss of a number of SUMO-1-modified protein isoforms, including PML. Recently, ICP0 has been shown to induce the accumulation of conjugated ubiquitin and function as a ubiquitin E3 ligase. However, certain aspects of the biochemistry, cell biology and the links between SUMO-1 conjugation/deconjugation and protein degradation remain unclear. For example, it is not currently known whether SUMO-1 deconjugation is a prerequisite for ubiquitination or degradation and, if so, by what mechanism this may occur. To help address these questions, a SUMO-specific protease (SENP1) was cloned and its expression and localization in relation to ICP0 examined. A cell line was established which constitutively expresses SUMO-1 to facilitate studies of localization and biochemistry. SENP1 localized to the nucleus mainly in discrete subdomains, a subset of which co-localized with the PML bodies. Both ICP0 and SENP1 protease promoted the loss of SUMO-1 from the nucleus, observed both for the endogenous species and the cell line expressing the epitope-tagged SUMO-1. The tagged SUMO-1 was recruited into high molecular mass conjugates in the cell line, and expression of SENP1 promoted loss of these species, including the modified species of PML. Finally, in co-transfection experiments ICP0 promoted the recruitment of SENP1 to nuclear domains, a result which was also observed early during infection. The significance of these findings is discussed in relation to the function of ICP0.
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Bermudez, Daniela, Priti Azad, Rómulo Figueroa-Mujíca, Gustavo Vizcardo-Galindo, Noemí Corante, Cristina Guerra-Giraldez, Gabriel G. Haddad, and Francisco C. Villafuerte. "Increased hypoxic proliferative response and gene expression in erythroid progenitor cells of Andean highlanders with chronic mountain sickness." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 318, no. 1 (January 1, 2020): R49—R56. http://dx.doi.org/10.1152/ajpregu.00250.2019.
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Excessive erythrocytosis (EE) is the main sign of chronic mountain sickness (CMS), a maladaptive clinical syndrome prevalent in Andean and other high-altitude populations worldwide. The pathophysiological mechanism of EE is still controversial, as physiological variability of systemic respiratory, cardiovascular, and hormonal responses to chronic hypoxemia complicates the identification of underlying causes. Induced pluripotent stem cells derived from CMS highlanders showed increased expression of genes relevant to the regulation of erythropoiesis, angiogenesis, cardiovascular, and steroid-hormone function that appear to explain the exaggerated erythropoietic response. However, the cellular response to hypoxia in native CMS cells is yet unknown. This study had three related aims: to determine the hypoxic proliferation of native erythroid progenitor burst-forming unit-erythroid (BFU-E) cells derived from CMS and non-CMS peripheral blood mononuclear cells; to examine their sentrin-specific protease 1 (SENP1), GATA-binding factor 1 (GATA1), erythropoietin (EPO), and EPO receptor (EPOR) expression; and to investigate the functional upstream role of SENP1 in native progenitor differentiation into erythroid precursors. Native CMS BFU-E colonies showed increased proliferation under hypoxic conditions compared with non-CMS cells, together with an upregulated expression of SENP1, GATA1, EPOR; and no difference in EPO expression. Knock-down of the SENP1 gene abolished the augmented proliferative response. Thus, we demonstrate that native CMS progenitor cells produce a larger proportion of erythroid precursors under hypoxia and that SENP1 is essential for proliferation. Our findings suggest a significant intrinsic component for developing EE in CMS highlanders at the cellular and gene expression level that could be further enhanced by systemic factors such as alterations in respiratory control, or differential hormonal patterns.
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Zhu, Xiaolong, Sha Ding, Cong Qiu, Yanna Shi, Lin Song, Yueyue Wang, Yuewen Wang, et al. "SUMOylation Negatively Regulates Angiogenesis by Targeting Endothelial NOTCH Signaling." Circulation Research 121, no. 6 (September 2017): 636–49. http://dx.doi.org/10.1161/circresaha.117.310696.
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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. Objective: The aim of this study was to investigate the role of SUMOylation in endothelial NOTCH signaling and angiogenesis. Methods and Results: Endothelial SENP1 (sentrin-specific protease 1) deletion, in newly generated endothelial SENP1 (the major protease of the SUMO system)–deficient mice, significantly delayed retinal vascularization by maintaining prolonged NOTCH1 signaling, as confirmed in cultured endothelial cells. An in vitro SUMOylation assay and immunoprecipitation revealed that when SENP1 associated with N1ICD (NOTCH1 intracellular domain), it functions as a deSUMOylase of N1ICD SUMOylation on conserved lysines. Immunoblot and immunoprecipitation analyses and dual-luciferase assays of natural and SUMO-conjugated/nonconjugated NOTCH1 forms demonstrated that SUMO conjugation facilitated NOTCH1 cleavage. This released N1ICD from the membrane and stabilized it for translocation to the nucleus where it functions as a cotranscriptional factor. Functionally, SENP1-mediated NOTCH1 deSUMOylation was required for NOTCH signal activation in response to DLL4 (Delta-like 4) stimulation. This in turn suppressed VEGF (vascular endothelial growth factor) receptor signaling and angiogenesis, as evidenced by immunoblotted signaling molecules and in vitro angiogenesis assays. Conclusions: These results establish reversible NOTCH1 SUMOylation as a regulatory mechanism in coordinating endothelial angiogenic signaling; SENP1 acts as a critical intrinsic mediator of this process. These findings may apply to NOTCH-regulated biological events in nonvascular tissues and provide a novel therapeutic strategy for vascular diseases and tumors.
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Kang, Heejung, Eui Tae Kim, Hye-Ra Lee, Jung-Jin Park, Yoon Young Go, Cheol Yong Choi, and Jin-Hyun Ahn. "Inhibition of SUMO-independent PML oligomerization by the human cytomegalovirus IE1 protein." Journal of General Virology 87, no. 8 (August 1, 2006): 2181–90. http://dx.doi.org/10.1099/vir.0.81787-0.
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In human cytomegalovirus-infected cells, the immediate-early IE1 protein disrupts the subnuclear structures known as the PML oncogenic domains or PODs, via the induction of PML desumoylation. This activity correlates with the functions of IE1 in transcriptional regulation and in the stimulation of lytic infection. Here, the effects of IE1 in induction of desumoylation of PML were characterized. IE1 did not interfere with the formation of sumoylated forms of PML in vitro. In in vitro assays using the sumoylated proteins, a SUMO-specific protease SENP1 desumoylated both PML and IE1. However, the IE1 proteins generated from bacteria or insect cells were unable to desumoylate PML in the same conditions. Although both IE1 and SUMO proteases such as SENP1, Axam and SuPr-1 efficiently desumoylated PML in co-transfection assays, they exerted different effects on the localization of PML. In cells transfected with either SENP1 or SuPr-1, the number of PML foci was reduced significantly and these remnant PML foci were devoid of SUMO-1 signals. However, in cells co-transfected with both SUMO proteases and IE1, these SUMO-independent PML foci were also completely disrupted. Furthermore, IE1, but not SENP1, was shown to disrupt the PML foci generated via transfection of a sumoylation-deficient mutant of PML. These data suggest that IE1 exhibits neither an inhibitory effect on sumoylation of PML nor intrinsic SUMO protease activity against PML in vitro. The finding that IE1 is capable of disrupting SUMO-independent PML aggregates suggests that inhibition of PML oligomerization by IE1 may play an important role in inducing PML desumoylation in vivo.
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Zhang, Rui, Qingxi Liu, Cuicui Lyu, Xing Gao, and Wenjian Ma. "Knockdown SENP1 Suppressed the Angiogenic Potential of Mesenchymal Stem Cells by Impacting CXCR4-Regulated MRTF-A SUMOylation and CCN1 Expression." Biomedicines 11, no. 3 (March 15, 2023): 914. http://dx.doi.org/10.3390/biomedicines11030914.
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The angiogenic potential of mesenchymal stem cells (MSCs) is critical for adult vascular regeneration and repair, which is regulated by various growth factors and cytokines. In the current study, we report that knockdown SUMO-specific peptidase 1 (SENP1) stimulated the SUMOylation of MRTF-A and prevented its translocation into the nucleus, leading to downregulation of the cytokine and angiogenic factor CCN1, which significantly impacted MSC-mediated angiogenesis and cell migration. Further studies showed that SENP1 knockdown also suppressed the expression of a chemokine receptor CXCR4, and overexpression of CXCR4 could partially abrogate MRTF-A SUMOylation and reestablish the CCN1 level. Mutation analysis confirmed that SUMOylation occurred on three lysine residues (Lys-499, Lys-576, and Lys-624) of MRTF-A. In addition, SENP1 knockdown abolished the synergistic co-activation of CCN1 between MRTF-A and histone acetyltransferase p300 by suppressing acetylation on histone3K9, histone3K14, and histone4. These results revealed an important signaling pathway to regulate MSC differentiation and angiogenesis by MRTF-A SUMOylation involving cytokine/chemokine activities mediated by CCN1 and CXCR4, which may potentially impact a variety of cellular processes such as revascularization, wound healing, and progression of cancer.
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Shi, Ting, Yuhui Han, Weihua Li, Yanlong Zhao, Yaqin Liu, Zhimin Huang, Shaoyong Lu, and Jian Zhang. "Exploring the Desumoylation Process of SENP1: A Study Combined MD Simulations with QM/MM Calculations on SENP1-SUMO1-RanGAP1." Journal of Chemical Information and Modeling 53, no. 9 (August 21, 2013): 2360–68. http://dx.doi.org/10.1021/ci4002487.
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Lin, Qiaoyu, Bin Yu, Xiangyang Wang, Shicong Zhu, Gan Zhao, Mingkang Jia, Fan Huang, et al. "K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells." Proceedings of the National Academy of Sciences 117, no. 19 (April 24, 2020): 10378–87. http://dx.doi.org/10.1073/pnas.1912984117.
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Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.
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Azad, Priti, Huiwen W. Zhao, Pedro J. Cabrales, Roy Ronen, Dan Zhou, Orit Poulsen, Otto Appenzeller, Yu Hsin Hsiao, Vineet Bafna, and Gabriel G. Haddad. "Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease." Journal of Experimental Medicine 213, no. 12 (November 7, 2016): 2729–44. http://dx.doi.org/10.1084/jem.20151920.
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In this study, because excessive polycythemia is a predominant trait in some high-altitude dwellers (chronic mountain sickness [CMS] or Monge’s disease) but not others living at the same altitude in the Andes, we took advantage of this human experiment of nature and used a combination of induced pluripotent stem cell technology, genomics, and molecular biology in this unique population to understand the molecular basis for hypoxia-induced excessive polycythemia. As compared with sea-level controls and non-CMS subjects who responded to hypoxia by increasing their RBCs modestly or not at all, respectively, CMS cells increased theirs remarkably (up to 60-fold). Although there was a switch from fetal to adult HgbA0 in all populations and a concomitant shift in oxygen binding, we found that CMS cells matured faster and had a higher efficiency and proliferative potential than non-CMS cells. We also established that SENP1 plays a critical role in the differential erythropoietic response of CMS and non-CMS subjects: we can convert the CMS phenotype into that of non-CMS and vice versa by altering SENP1 levels. We also demonstrated that GATA1 is an essential downstream target of SENP1 and that the differential expression and response of GATA1 and Bcl-xL are a key mechanism underlying CMS pathology.
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Bawa-Khalfe, Tasneem, Jinke Cheng, Sue-Hwa Lin, Michael M. Ittmann, and Edward T. H. Yeh. "SENP1 Induces Prostatic Intraepithelial Neoplasia through Multiple Mechanisms." Journal of Biological Chemistry 285, no. 33 (June 15, 2010): 25859–66. http://dx.doi.org/10.1074/jbc.m110.134874.
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Xiang-ming, Yan, Xu Zhi-qiang, Zhang Ting, Wang Jian, Pan Jian, Yuan Li-qun, Fu Ming-cui, Xia Hong-liang, Cao Xu, and Zhou Yun. "SENP1 regulates cell migration and invasion in neuroblastoma." Biotechnology and Applied Biochemistry 63, no. 3 (August 18, 2015): 435–40. http://dx.doi.org/10.1002/bab.1375.
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Itahana, Yoko, Edward T. H. Yeh, and Yanping Zhang. "Nucleocytoplasmic Shuttling Modulates Activity and Ubiquitination-Dependent Turnover of SUMO-Specific Protease 2." Molecular and Cellular Biology 26, no. 12 (June 15, 2006): 4675–89. http://dx.doi.org/10.1128/mcb.01830-05.
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ABSTRACT Small ubiquitin-related modifier (SUMO) proteins are conjugated to numerous polypeptides in cells, and attachment of SUMO plays important roles in regulating the activity, stability, and subcellular localization of modified proteins. SUMO modification of proteins is a dynamic and reversible process. A family of SUMO-specific proteases catalyzes the deconjugation of SUMO-modified proteins. Members of the Sentrin (also known as SUMO)-specific protease (SENP) family have been characterized with unique subcellular localizations. However, little is known about the functional significance of or the regulatory mechanism derived from the specific localizations of the SENPs. Here we identify a bipartite nuclear localization signal (NLS) and a CRM1-dependent nuclear export signal (NES) in the SUMO protease SENP2. Both the NLS and the NES are located in the nonhomologous domains of SENP2 and are not conserved among other members of the SENP family. Using a series of SENP2 mutants and a heterokaryon assay, we demonstrate that SENP2 shuttles between the nucleus and the cytoplasm and that the shuttling is blocked by mutations in the NES or by treating cells with leptomycin B. We show that SENP2 can be polyubiquitinated in vivo and degraded through proteolysis. Restricting SENP2 in the nucleus by mutations in the NES impairs its polyubiquitination, whereas a cytoplasm-localized SENP2 made by introducing mutations in the NLS can be efficiently polyubiquitinated, suggesting that SENP2 is ubiquitinated in the cytoplasm. Finally, treating cells with MG132 leads to accumulation of polyubiquitinated SENP2, indicating that SENP2 is degraded through the 26S proteolysis pathway. Thus, the function of SENP2 is regulated by both nucleocytoplasmic shuttling and polyubiquitin-mediated degradation.
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Xu, Yangqi, Wenwen Cai, Shaoming Sang, Xiaoqin Cheng, Boru Jin, Xiangteng Zhao, and Chunjiu Zhong. "The Dynamic SUMOylation Changes and Their Potential Role in the Senescence of APOE4 Mice." Biomedicines 12, no. 1 (December 20, 2023): 16. http://dx.doi.org/10.3390/biomedicines12010016.
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The ε4 allele of apolipoprotein E (APOE4) and aging are the major risk factors for Alzheimer’s disease (AD). SUMOylation is intimately linked to the development of AD and the aging process. However, the SUMOylation status in APOE4 mice has not been uncovered. In this study, we investigated SENP1 and SUMOylation changes in the brains of aged APOE3 and APOE4 mice, aiming to understand their potential impact on mitochondrial metabolism and their contribution to cellular senescence in APOE4 mice. Concurrently, SUMO1-conjugated protein levels decreased, while SUMO2/3-conjugated protein levels increased relatively with the aging of APOE4 mice. This suggests that the equilibrium between the SUMOylation and deSUMOylation processes may be associated with senescence and longevity. Our findings highlight the significant roles of SENP1 and SUMOylation changes in APOE4-driven pathology and the aging process.
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Bawa-Khalfe, Tasneem, Feng-Ming Yang, Joan Ritho, Hui-Kuan Lin, Jinke Cheng, and Edward T. H. Yeh. "SENP1 regulates PTEN stability to dictate prostate cancer development." Oncotarget 8, no. 11 (November 10, 2016): 17651–64. http://dx.doi.org/10.18632/oncotarget.13283.
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Yu, Luyang, Weidong Ji, Haifeng Zhang, Matthew J. Renda, Yun He, Sharon Lin, Ee-chun Cheng, Hong Chen, Diane S. Krause, and Wang Min. "SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis." Journal of Cell Biology 189, no. 4 (May 17, 2010): i12. http://dx.doi.org/10.1083/jcb1894oia12.
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