Critical Function of Siah2 in Tumorigenesis
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HIPK2–P53ser46 Damage Response Pathway Is Involved in Temozolomide-Induced Glioblastoma Cell Death Yang He, Wynand P
Published OnlineFirst February 22, 2019; DOI: 10.1158/1541-7786.MCR-18-1306 Cell Fate Decisions Molecular Cancer Research The SIAH1–HIPK2–p53ser46 Damage Response Pathway is Involved in Temozolomide-Induced Glioblastoma Cell Death Yang He, Wynand P. Roos, Qianchao Wu, Thomas G. Hofmann, and Bernd Kaina Abstract Patients suffering from glioblastoma have a dismal prog- in chromatin-immunoprecipitation experiments, in which nosis, indicating the need for new therapeutic targets. Here p-p53ser46 binding to the Fas promotor was regulated by we provide evidence that the DNA damage kinase HIPK2 HIPK2. Other pro-apoptotic proteins such as PUMA, and its negative regulatory E3-ubiquitin ligase SIAH1 are NOXA, BAX, and PTEN were not affected in HIPK2kd, and critical factors controlling temozolomide-induced cell also double-strand breaks following temozolomide remain- death. We show that HIPK2 downregulation (HIPK2kd) ed unaffected. We further show that downregulation of significantly reduces the level of apoptosis. This was not the HIPK2 inactivator SIAH1 significantly ameliorates the case in glioblastoma cells expressing the repair protein temozolomide-induced apoptosis, suggesting that the MGMT, suggesting that the primary DNA lesion responsible ATM/ATR target SIAH1 together with HIPK2 plays a pro- 6 for triggering HIPK2-mediated apoptosis is O -methylguanine. apoptotic role in glioma cells exhibiting p53wt status. A Upon temozolomide treatment, p53 becomes phosphory- database analysis revealed that SIAH1, but not SIAH2, is lated whereby HIPK2kd had impact exclusively on ser46, significantly overexpressed in glioblastomas. but not ser15. Searching for the transcriptional target of p-p53ser46, we identified the death receptor FAS (CD95, Implications: The identification of a novel apoptotic APO-1) being involved. -
Inside Lab Invest
Laboratory Investigation (2012) 0092, 000-000800-801 © 2012 USCAP, Inc All rights reserved 0023-6837/060023-6837/12 $30.00$32.00 INSIDE LLII doi:10.1038/labinvest.2012.82 New gastric carcinoma forestomach and the glandular epithelium advantage of the Akita−/− mouse model of mouse model of the lesser curvature. These changes type 1 diabetes to examine the effects of were not observed at the junction of the uncontrolled hyperglycemia on oral health. See page 883 forestomach and the greater curvature. The investigators demonstrated Furthermore, no histological changes that, although teeth develop normally were observed in heterozygous Smad3+/− in these mice, they exhibit significant heterozygotes or age-matched wild- oral pathology after birth. Beginning type littermate controls. At 10 months, at 4 weeks after birth, the mice began metaplastic lesions in Smad−/− mice to show increased wearing of enamel progressed to high-grade dysplasia. characterized by a modest reduction of Interestingly, there was also an association enamel and dentin. Hypomineralization between the areas of metaplasia and and enamel attrition were accompanied gastritis cystica profunda, which the by microabscesses that progressed to authors interpreted as invading glands, significant tooth destruction and bone although the relationship to gastric loss around the roots of affected teeth. carcinoma was unclear. In summary, the Mechanistically, Akita−/− mice were found authors have developed a novel Smad to have impaired saliva production, knockout mouse model in which to study probably due to a neurologic defect. the pathogenesis of adenocarcinoma of Cell culture experiments using pulp cells the proximal stomach. showed that high glucose inhibited both proliferation and differentiation. -
Supplementary Materials
Supplementary materials Supplementary Table S1: MGNC compound library Ingredien Molecule Caco- Mol ID MW AlogP OB (%) BBB DL FASA- HL t Name Name 2 shengdi MOL012254 campesterol 400.8 7.63 37.58 1.34 0.98 0.7 0.21 20.2 shengdi MOL000519 coniferin 314.4 3.16 31.11 0.42 -0.2 0.3 0.27 74.6 beta- shengdi MOL000359 414.8 8.08 36.91 1.32 0.99 0.8 0.23 20.2 sitosterol pachymic shengdi MOL000289 528.9 6.54 33.63 0.1 -0.6 0.8 0 9.27 acid Poricoic acid shengdi MOL000291 484.7 5.64 30.52 -0.08 -0.9 0.8 0 8.67 B Chrysanthem shengdi MOL004492 585 8.24 38.72 0.51 -1 0.6 0.3 17.5 axanthin 20- shengdi MOL011455 Hexadecano 418.6 1.91 32.7 -0.24 -0.4 0.7 0.29 104 ylingenol huanglian MOL001454 berberine 336.4 3.45 36.86 1.24 0.57 0.8 0.19 6.57 huanglian MOL013352 Obacunone 454.6 2.68 43.29 0.01 -0.4 0.8 0.31 -13 huanglian MOL002894 berberrubine 322.4 3.2 35.74 1.07 0.17 0.7 0.24 6.46 huanglian MOL002897 epiberberine 336.4 3.45 43.09 1.17 0.4 0.8 0.19 6.1 huanglian MOL002903 (R)-Canadine 339.4 3.4 55.37 1.04 0.57 0.8 0.2 6.41 huanglian MOL002904 Berlambine 351.4 2.49 36.68 0.97 0.17 0.8 0.28 7.33 Corchorosid huanglian MOL002907 404.6 1.34 105 -0.91 -1.3 0.8 0.29 6.68 e A_qt Magnogrand huanglian MOL000622 266.4 1.18 63.71 0.02 -0.2 0.2 0.3 3.17 iolide huanglian MOL000762 Palmidin A 510.5 4.52 35.36 -0.38 -1.5 0.7 0.39 33.2 huanglian MOL000785 palmatine 352.4 3.65 64.6 1.33 0.37 0.7 0.13 2.25 huanglian MOL000098 quercetin 302.3 1.5 46.43 0.05 -0.8 0.3 0.38 14.4 huanglian MOL001458 coptisine 320.3 3.25 30.67 1.21 0.32 0.9 0.26 9.33 huanglian MOL002668 Worenine -
Is Glyceraldehyde-3-Phosphate Dehydrogenase a Central Redox Mediator?
1 Is glyceraldehyde-3-phosphate dehydrogenase a central redox mediator? 2 Grace Russell, David Veal, John T. Hancock* 3 Department of Applied Sciences, University of the West of England, Bristol, 4 UK. 5 *Correspondence: 6 Prof. John T. Hancock 7 Faculty of Health and Applied Sciences, 8 University of the West of England, Bristol, BS16 1QY, UK. 9 [email protected] 10 11 SHORT TITLE | Redox and GAPDH 12 13 ABSTRACT 14 D-Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an immensely important 15 enzyme carrying out a vital step in glycolysis and is found in all living organisms. 16 Although there are several isoforms identified in many species, it is now recognized 17 that cytosolic GAPDH has numerous moonlighting roles and is found in a variety of 18 intracellular locations, but also is associated with external membranes and the 19 extracellular environment. The switch of GAPDH function, from what would be 20 considered as its main metabolic role, to its alternate activities, is often under the 21 influence of redox active compounds. Reactive oxygen species (ROS), such as 22 hydrogen peroxide, along with reactive nitrogen species (RNS), such as nitric oxide, 23 are produced by a variety of mechanisms in cells, including from metabolic 24 processes, with their accumulation in cells being dramatically increased under stress 25 conditions. Overall, such reactive compounds contribute to the redox signaling of the 26 cell. Commonly redox signaling leads to post-translational modification of proteins, 27 often on the thiol groups of cysteine residues. In GAPDH the active site cysteine can 28 be modified in a variety of ways, but of pertinence, can be altered by both ROS and 29 RNS, as well as hydrogen sulfide and glutathione. -
Siah - a Promising Anti-Cancer Target
Author Manuscript Published OnlineFirst on March 1, 2013; DOI: 10.1158/0008-5472.CAN-12-4348 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Siah - a promising anti-cancer target Christina SF Wong1 and Andreas Möller1 1 Tumour Microenvironment Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Queensland 4006, Australia. Corresponding Author: Andreas Möller ([email protected]) Running title: Siah and Cancer Keywords: Siah1, Siah2, E3 Ubiquitin ligases, Cancer Potential conflict of interest: The authors declare no conflict of interest. Word count: Abstract: 100 words; Text: 2590 words; Number of Figures: 1; Number of Tables: 1 1 Downloaded from cancerres.aacrjournals.org on September 29, 2021. © 2013 American Association for Cancer Research. Author Manuscript Published OnlineFirst on March 1, 2013; DOI: 10.1158/0008-5472.CAN-12-4348 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract: Siah ubiquitin ligases play important roles in a number of signaling pathways involved in the progression and spread of cancer in cell-based models but their role in tumor progression remains controversial. Siah proteins have been described to be both oncogenic as well as tumor-suppressive in a variety of patient cohort studies and animal cancer models. This review collates the current knowledge of Siah in cancer progression and identifies potential methods of translation of these findings into the clinic. Furthermore, key experiments needed to close the gaps in our understanding of the role Siah proteins play in tumor progression are suggested. 2 Downloaded from cancerres.aacrjournals.org on September 29, 2021. -
SIAH2-Mediated and Organ-Specific Restriction of HO-1 Expression by A
www.nature.com/scientificreports OPEN SIAH2-mediated and organ-specifc restriction of HO-1 expression by a dual mechanism Shashipavan Chillappagari1*, Ratnal Belapurkar1, Andreas Möller2, Nicole Molenda3, Michael Kracht4, Susanne Rohrbach3 & M. Lienhard Schmitz1* The intracellular levels of the cytoprotective enzyme heme oxygenase-1 (HO-1) are tightly controlled. Here, we reveal a novel mechanism preventing the exaggerated expression of HO-1. The analysis of mice with a knock-out in the ubiquitin E3 ligase seven in absentia homolog 2 (SIAH2) showed elevated HO-1 protein levels in specifc organs such as heart, kidney and skeletal muscle. Increased HO-1 protein amounts were also seen in human cells deleted for the SIAH2 gene. The higher HO-1 levels are not only due to an increased protein stability but also to elevated expression of the HO-1 encoding HMOX1 gene, which depends on the transcription factor nuclear factor E2-related factor 2 (NRF2), a known SIAH2 target. Dependent on its RING (really interesting new gene) domain, expression of SIAH2 mediates proteasome-dependent degradation of its interaction partner HO-1. Additionally SIAH2-defcient cells are also characterized by reduced expression levels of glutathione peroxidase 4 (GPX4), rendering the knock-out cells more sensitive to ferroptosis. Ubiquitin E3 ligases regulate the activity and turnover of many target proteins, thus controlling key features such as metabolism, stress signaling and cell cycle progression1. Te RING family of ubiquitin E3 ligases comprises the SIAH family. Te human genome encodes SIAH1 and the homologous SIAH2 protein as well as SIAH3, which lacks a functional RING domain and is only expressed in a limited subset of cancer cell lines2. -
TRB3 Is Elevated in Psoriasis Vulgaris Lesions and Mediates Hacat Cells Proliferation in Vitro Xiao-Jing Yu, Tie-Jun Song, Lu-Wei Zhang, Ying Su, Ke-Yu Wang, Qing Sun
Brief report J Investig Med: first published as 10.1136/jim-2017-000453 on 7 August 2017. Downloaded from TRB3 is elevated in psoriasis vulgaris lesions and mediates HaCaT cells proliferation in vitro Xiao-Jing Yu, Tie-Jun Song, Lu-Wei Zhang, Ying Su, Ke-Yu Wang, Qing Sun Department of Dermatology, ABSTRACT It presents clinically as a sharply demarcated Qilu Hospital of Shandong Psoriasis is a chronic skin disease characterized erythematous plaque with silvery white scales. University, Jinan, Shandong, Histologically, it is characterized by hyperkera- China by abnormal keratinocyte proliferation and differentiation, inflammation, and angiogenesis. tosis, parakeratosis, acanthosis of the epidermis, Correspondence to Overexpression of tribbles homolog3 (TRB3), which tortuous and dilated vessels, and an inflamma- Dr Qing Sun, Department of belongs to the tribbles family of pseudokinases, has tory infiltrate composed mostly of lymphocytes. Dermatology, Qilu Hospital, been found in several human tumors and metabolic The pathogenesis of psoriasis is complex and the University of Shandong, diseases, but its role in psoriasis has not been fully exact mechanism remains elusive, but abnormal Jinan 250012, China; proliferation of keratinocytes is an important sunqing7226@ 163. com clarified. The aim of this study is to investigate the expression of TRB3 in psoriasis and explore its roles mechanism of psoriasis, resulting in epidermal Received 25 February 2017 in the proliferation of keratinocytes. Twenty-four hyperplasia and a morphologic characteristic of Revised 28 June 2017 patients with psoriasis vulgaris were recruited for the psoriasis.16 Numerous well established antipso- Accepted 2 July 2017 study. Diagnosis of psoriasis was based on clinical riatic treatments, including phototherapy, oral Published Online First 7 August 2017 and histologic examinations. -
Rabbit Anti-SIAH1/FITC Conjugated Antibody-SL3596R-FITC
SunLong Biotech Co.,LTD Tel: 0086-571- 56623320 Fax:0086-571- 56623318 E-mail:[email protected] www.sunlongbiotech.com Rabbit Anti-SIAH1/FITC Conjugated antibody SL3596R-FITC Product Name: Anti-SIAH1/FITC Chinese Name: FITC标记的Ubiquitin连接酶Siah1抗体 hSIAH1; HUMSIAH; Seven in absentia homolog 1 (Drosophila); Seven in absentia homolog 1; Siah 1; Siah 1a; Ubiquitin ligase SIAH1; E3 ubiquitin-protein ligase SIAH1; Alias: Seven in absentia homolog 1; Siah-1; Siah-1a; Siah E3 ubiquitin protein ligase 1; SIAH1_HUMAN; SIAH1A. Organism Species: Rabbit Clonality: Polyclonal React Species: Human,Mouse,Rat,Chicken,Dog,Pig,Cow,Horse,Rabbit, IF=1:50-200 Applications: not yet tested in other applications. optimal dilutions/concentrations should be determined by the end user. Molecular weight: 34kDa Form: Lyophilized or Liquid Concentration: 1mg/ml immunogen: KLH conjugated synthetic peptide derived from human SIAH1 Lsotype: IgG Purification: affinitywww.sunlongbiotech.com purified by Protein A Storage Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Store at -20 °C for one year. Avoid repeated freeze/thaw cycles. The lyophilized antibody is stable at room temperature for at least one month and for greater than a year Storage: when kept at -20°C. When reconstituted in sterile pH 7.4 0.01M PBS or diluent of antibody the antibody is stable for at least two weeks at 2-4 °C. background: This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome- Product Detail: mediated degradation of specific proteins. -
SIAH2 Antibody
Efficient Professional Protein and Antibody Platforms SIAH2 Antibody Basic information: Catalog No.: UPA61750 Source: Rabbit Size: 50ul/100ul Clonality: polyclonal Concentration: 1mg/ml Isotype: Rabbit IgG Purification: affinity purified by Protein A Useful Information: Applications: WB:1:500-2000 Reactivity: Human, Mouse, Rat, Chicken, Dog, Pig, Cow, Horse, Rabbit Specificity: This antibody recognizes SIAH2 protein. Immunogen: KLH conjugated synthetic peptide derived from human SIAH2 201-300/324 E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioe- ster and then directly transfers the ubiquitin to targeted substrates. Medi- ates E3 ubiquitin ligase activity either through direct binding to substrates or by functioning as the essential RING domain subunit of larger E3 com- plexes. Triggers the ubiquitin-mediated degradation of many substrates, in- Description: cluding proteins involved in transcription regulation (POU2AF1, PML, NCOR1), a cell surface receptor (DCC), an antiapoptotic protein (BAG1), and a protein involved in synaptic vesicle function in neurons (SYP). Mediates ubiquitination and proteasomal degradation of DYRK2 in response to hy- poxia. It is thereby involved in apoptosis, tumor suppression, cell cycle, transcription and signaling processes. Has some overlapping function with SIAH1. Triggers the ubiquitin-mediated degradation of TRAF2, whereas SI- AH1 can not. Promotes monoubiquitination of SNCA. Uniprot: O43255 Human BiowMW: 35 KDa Buffer: 0.01M TBS(pH7.4) with 1% BSA, 0.03% Proclin300 and 50% Glycerol. Storage: Store at 4°C short term and -20°C long term. Avoid freeze-thaw cycles. Note: For research use only, not for use in diagnostic procedure. -
Expression and Purification of the Predicted PEG10 Aspartyl Protease
Expression and purification of the predicted PEG10 aspartyl protease domain Caillan Crowe-McAuliffe A thesis submitted for the degree of Master of Science Department of Biochemistry University of Otago, Dunedin, New Zealand. April 2013 Abstract Paternally Expressed Gene 10 (PEG10) is an imprinted, retrotransposon-derived gene found in mammals. Although many of the retrotransposon domains have become de- generated in PEG10, a predicted retroviral-type aspartyl protease (AP) domain has been highly conserved. Retroviral-type APs play a crucial role in the replication of some retroviruses such as the Human Immunodeficiency Virus (HIV) and are there- fore important drug targets. Consequently, extensive biochemical and structural data are available for this class of proteins, although the vast majority of this has been gath- ered from only a small number of retroviral enzymes. Preliminary evidence indicates that the PEG10 AP is an active protease, although proteolysis by this enzyme has yet to be observed in vitro (Clark et al., 2007). This study aimed to express, purify, and characterise the predicted PEG10 AP. A number of PEG10 AP clones, each with different termini and across more than one recombinant expression system, were expressed to produce the PEG10 AP domain in E. coli. The majority of expressed proteins were largely insoluble and unsuitable for further characterisation. One clone, however, produced soluble PEG10 AP in sufficient quantities for purification and further analysis. Several lines of evidence indicated that the purified protein was dimeric in solution, consistent with the quaternary structure of other retroviral-type APs. The results presented in this thesis support the hypothesis that the PEG10 AP is active and has retained characteristics from the ancestral retrotransposon enzyme. -
SIAH1-Mediated RPS3 Ubiquitination Contributes to Chemosensitivity in Epithelial Ovarian Cancer
SIAH1-Mediated RPS3 Ubiquitination Contributes to Chemosensitivity in Epithelial Ovarian Cancer Lu Chen Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Wujiang Gao Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Chunli Sha Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Taoqiong Li Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Li Lin Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Hong Wei Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Qi Chen Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Jie Xing Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Mengxue Zhang Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Shijie Zhao Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Wenlin Xu Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Yuefeng Li Jiangsu University Hospital Xiaolan Zhu ( [email protected] ) Zhenjiang Fourth Peoples Hospital and Zhenjiang Women and Childrens Hospital Research Keywords: EOC, chemoresistance, SIAH1, RPS3,NF-κB Posted Date: July 20th, 2021 Page 1/27 DOI: https://doi.org/10.21203/rs.3.rs-697379/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 2/27 Abstract Background: The E3 ligase SIAH1 is deregulated in human cancers and correlated with poor prognosis, but its contributions to chemoresistance in epithelial ovarian cancer (EOC) are not evident. Methods: SIAHI, RPS3, NF-κB (P65), FLAG and GFP protein levels were assessed by western blotting (WB) or immunohistochemistry (IHC). The mRNA levels were revealed by qRT-PCR. -
Monoclonal Anti-Siah2 Antibody Produced in Mouse
Monoclonal Anti-Siah2 Clone Siah2-369 Purified Mouse Immunoglobulin Product Number S 7945 Product Description functions. Siah2 was implicated in the regulation of key Monoclonal Anti-Siah2 (mouse IgG1 isotype) is derived proteins in the immune system such as TRAF, Vav1, from the hybridoma Siah2-369 produced by the fusion of and OBF-1. Knockout mice of Siah1a exhibit severe mouse myeloma cells (NS1 cell) and splenocytes from growth retardation, early lethality and exhibit a block in BALB/c mice immunized with a synthetic peptide meiotic cell division during meiosis I of spermato- corresponding to amino acids 2-17 of human Siah2, genesis. However, knockout mice of Siah2 are largely conjugated to KLH. The isotype is determined using a phenotypically normal.4 Siah1a and Siah2 are important double diffusion immunoassay using Mouse Monoclonal for the regulation of the PHD enzymes (prolylhydrox- Antibody Isotyping Reagents (Sigma ISO-2). ylases) that are responsible for the prolyhydroxylation of HIF a protein under hypoxia conditions.5 Monoclonal Anti-Siah2 recognizes human, monkey, bovine, canine, hamster, and mouse Siah2 (~37 kDa). Reagent The antibody can be used in ELISA, immunocyto- The antibody is supplied as a solution in 0.01 M phos- chemistry, and immunoblotting. phate buffered saline, pH 7.4, containing 15 mM sodium azide. Ubiquitination of proteins is an important process in the pathway leading to their degradation through the Antibody Concentration: ~2 mg/mL proteasome. The Siah (Seven in absentia homologue) protein family belongs to the E3 ubiquitin ligase protein Precautions and Disclaimer family. These proteins can mediate E3 ubiquitin ligase Due to the sodium azide content, a material safety data activity either by direct binding to protein targets or by sheet (MSDS) for this product has been sent to the functioning as the essential RING domain subunit of attention of the safety officer of your institution.