Critical Function for SIP, a Ubiquitin E3 Ligase Component of the B-Catenin Degradation Pathway, for Thymocyte Development and G1 Checkpoint
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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. -
Cacybp (NM 009786) Mouse Tagged ORF Clone Product Data
OriGene Technologies, Inc. 9620 Medical Center Drive, Ste 200 Rockville, MD 20850, US Phone: +1-888-267-4436 [email protected] EU: [email protected] CN: [email protected] Product datasheet for MR202748 Cacybp (NM_009786) Mouse Tagged ORF Clone Product data: Product Type: Expression Plasmids Product Name: Cacybp (NM_009786) Mouse Tagged ORF Clone Tag: Myc-DDK Symbol: Cacybp Synonyms: SIP Vector: pCMV6-Entry (PS100001) E. coli Selection: Kanamycin (25 ug/mL) Cell Selection: Neomycin ORF Nucleotide >MR202748 ORF sequence Sequence: Red=Cloning site Blue=ORF Green=Tags(s) TTTTGTAATACGACTCACTATAGGGCGGCCGGGAATTCGTCGACTGGATCCGGTACCGAGGAGATCTGCC GCCGCGATCGCC ATGGCTTCCGTTTTGGAAGAGTTGCAGAAAGACCTAGAAGAGGTCAAAGTATTGCTGGAAAAGTCCACTA GGAAAAGACTACGTGATACTCTTACAAGTGAAAAGTCCAAGATTGAGACGGAACTCAAGAACAAGATGCA ACAGAAGTCGCAGAAGAAACCAGAACTTGATAATGAAAAGCCAGCTGCTGTGGTTGCTCCTCTTACAACA GGATACACCGTGAAAATCAGTAATTATGGATGGGATCAGTCAGATAAGTTTGTGAAAATCTACATTACCT TGACTGGCGTCCATCAGGTGCCCACTGAGAACGTGCAGGTGCACTTCACAGAGAGGTCATTTGATCTTCT GGTAAAAAACCTCAATGGCAAGAATTACTCCATGATTGTGAACAATCTTTTGAAACCTATCTCTGTGGAA AGCAGTTCAAAAAAAGTCAAGACTGATACAGTAATTATTCTATGTAGAAAGAAAGCAGAAAACACAAGAT GGGACTACTTAACACAGGTGGAAAAGGAATGCAAAGAGAAAGAAAAGCCTTCCTACGACACGGAGGCAGA CCCTAGTGAGGGATTAATGAATGTTCTAAAGAAAATTTATGAAGACGGAGACGATGATATGAAGCGAACC ATTAATAAAGCGTGGGTGGAATCCAGAGAGAAGCAAGCCAGAGAAGACACGGAATTT ACGCGTACGCGGCCGCTCGAGCAGAAACTCATCTCAGAAGAGGATCTGGCAGCAAATGATATCCTGGATT ACAAGGATGACGACGATAAGGTTTAA This product is to be used for laboratory only. Not for diagnostic or therapeutic use. View online -
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. -
Critical Function of Siah2 in Tumorigenesis
AIMS Molecular Science, 4(4): 415-423 DOI: 10.3934/molsci.2017.4.415 Received 31 July 2017, Accepted 21 September 2017, Published 11 October 2017 http://www.aimspress.com/journal/Molecular Review Critical function of Siah2 in tumorigenesis Kazunobu Baba, Tadaaki Miyazaki* Department of Probiotics Immunology, Institute for Genetic Medicine, Hokkaido University, North 15 West 7, Kita-ku, Sapporo City, Hokkaido, Japan * Correspondence: Email: [email protected]; Tel: 81-011-706-8095. Abstract: The seven in absentia homolog (Siah) family proteins are components of E3 RING zinc finger ubiquitin ligase complexes that catalyze the ubiquitination of proteins. Siah proteins target their substrates for proteasomal degradation. Evidence is growing that Siah proteins are implicated in the progression of various cancer cells and play a critical role in angiogenesis and tumorigenesis, particularly through Ras, p53, estrogen, and hypoxia inducible factor (HIF)-mediated signaling pathways in response to DNA damage or hypoxia. Keywords: Siah2; Nrf2; ROS metabolism; Hypoxia 1. Introduction The seven in absentia (Sina) gene was initially identified to be critical for photoreceptor cell development in Drosophila [1]. As its mammalian orthologs, murine and human homologs of the Sina gene have also been identified. In Xenopus and mice, Sina homologs (Siahs) were isolated as three Siah proteins, Siah1a, Siah1b, and Siah2, which are encoded by different genes [2]. In contrast, the human Siah proteins consist of two homologs, Siah1 and Siah2, which are encoded by the SIAH1 and SIAH2 genes, respectively [3]. Siah1 and Siah2 have the high sequence similarity of their N-terminal RING finger domain, central cysteine-rich domain, and C-terminal substrate binding domain (SBD); however, Siah1 and Siah2 apparently have distinct but overlapping functions as proteins of a tumor suppressor gene and a proto-oncogene, respectively (Figure 1) [4]. -
Aneuploidy: Using Genetic Instability to Preserve a Haploid Genome?
Health Science Campus FINAL APPROVAL OF DISSERTATION Doctor of Philosophy in Biomedical Science (Cancer Biology) Aneuploidy: Using genetic instability to preserve a haploid genome? Submitted by: Ramona Ramdath In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Science Examination Committee Signature/Date Major Advisor: David Allison, M.D., Ph.D. Academic James Trempe, Ph.D. Advisory Committee: David Giovanucci, Ph.D. Randall Ruch, Ph.D. Ronald Mellgren, Ph.D. Senior Associate Dean College of Graduate Studies Michael S. Bisesi, Ph.D. Date of Defense: April 10, 2009 Aneuploidy: Using genetic instability to preserve a haploid genome? Ramona Ramdath University of Toledo, Health Science Campus 2009 Dedication I dedicate this dissertation to my grandfather who died of lung cancer two years ago, but who always instilled in us the value and importance of education. And to my mom and sister, both of whom have been pillars of support and stimulating conversations. To my sister, Rehanna, especially- I hope this inspires you to achieve all that you want to in life, academically and otherwise. ii Acknowledgements As we go through these academic journeys, there are so many along the way that make an impact not only on our work, but on our lives as well, and I would like to say a heartfelt thank you to all of those people: My Committee members- Dr. James Trempe, Dr. David Giovanucchi, Dr. Ronald Mellgren and Dr. Randall Ruch for their guidance, suggestions, support and confidence in me. My major advisor- Dr. David Allison, for his constructive criticism and positive reinforcement. -
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. -
Identification of Differentially Expressed Genes in Human Bladder Cancer Through Genome-Wide Gene Expression Profiling
521-531 24/7/06 18:28 Page 521 ONCOLOGY REPORTS 16: 521-531, 2006 521 Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling KAZUMORI KAWAKAMI1,3, HIDEKI ENOKIDA1, TOKUSHI TACHIWADA1, TAKENARI GOTANDA1, KENGO TSUNEYOSHI1, HIROYUKI KUBO1, KENRYU NISHIYAMA1, MASAKI TAKIGUCHI2, MASAYUKI NAKAGAWA1 and NAOHIKO SEKI3 1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520; Departments of 2Biochemistry and Genetics, and 3Functional Genomics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Received February 15, 2006; Accepted April 27, 2006 Abstract. Large-scale gene expression profiling is an effective CKS2 gene not only as a potential biomarker for diagnosing, strategy for understanding the progression of bladder cancer but also for staging human BC. This is the first report (BC). The aim of this study was to identify genes that are demonstrating that CKS2 expression is strongly correlated expressed differently in the course of BC progression and to with the progression of human BC. establish new biomarkers for BC. Specimens from 21 patients with pathologically confirmed superficial (n=10) or Introduction invasive (n=11) BC and 4 normal bladder samples were studied; samples from 14 of the 21 BC samples were subjected Bladder cancer (BC) is among the 5 most common to microarray analysis. The validity of the microarray results malignancies worldwide, and the 2nd most common tumor of was verified by real-time RT-PCR. Of the 136 up-regulated the genitourinary tract and the 2nd most common cause of genes we detected, 21 were present in all 14 BCs examined death in patients with cancer of the urinary tract (1-7). -
In This Table Protein Name, Uniprot Code, Gene Name P-Value
Supplementary Table S1: In this table protein name, uniprot code, gene name p-value and Fold change (FC) for each comparison are shown, for 299 of the 301 significantly regulated proteins found in both comparisons (p-value<0.01, fold change (FC) >+/-0.37) ALS versus control and FTLD-U versus control. Two uncharacterized proteins have been excluded from this list Protein name Uniprot Gene name p value FC FTLD-U p value FC ALS FTLD-U ALS Cytochrome b-c1 complex P14927 UQCRB 1.534E-03 -1.591E+00 6.005E-04 -1.639E+00 subunit 7 NADH dehydrogenase O95182 NDUFA7 4.127E-04 -9.471E-01 3.467E-05 -1.643E+00 [ubiquinone] 1 alpha subcomplex subunit 7 NADH dehydrogenase O43678 NDUFA2 3.230E-04 -9.145E-01 2.113E-04 -1.450E+00 [ubiquinone] 1 alpha subcomplex subunit 2 NADH dehydrogenase O43920 NDUFS5 1.769E-04 -8.829E-01 3.235E-05 -1.007E+00 [ubiquinone] iron-sulfur protein 5 ARF GTPase-activating A0A0C4DGN6 GIT1 1.306E-03 -8.810E-01 1.115E-03 -7.228E-01 protein GIT1 Methylglutaconyl-CoA Q13825 AUH 6.097E-04 -7.666E-01 5.619E-06 -1.178E+00 hydratase, mitochondrial ADP/ATP translocase 1 P12235 SLC25A4 6.068E-03 -6.095E-01 3.595E-04 -1.011E+00 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 MIC J3QTA6 CHCHD6 1.090E-04 -5.913E-01 2.124E-03 -5.948E-01 Protein kinase C and casein Q9BY11 PACSIN1 3.837E-03 -5.863E-01 3.680E-06 -1.824E+00 kinase substrate in neurons protein 1 Tubulin polymerization- O94811 TPPP 6.466E-03 -5.755E-01 6.943E-06 -1.169E+00 promoting protein MIC C9JRZ6 CHCHD3 2.912E-02 -6.187E-01 2.195E-03 -9.781E-01 Mitochondrial 2- -
S100A6 and Its Brain Ligands in Neurodegenerative Disorders
International Journal of Molecular Sciences Review S100A6 and Its Brain Ligands in Neurodegenerative Disorders Anna Filipek * and Wiesława Le´sniak Nencki Institute of Experimental Biology, Polish Academy of Sciences, 3 Pasteur Street, 02-093 Warsaw, Poland; [email protected] * Correspondence: a.fi[email protected] Received: 13 May 2020; Accepted: 29 May 2020; Published: 1 June 2020 Abstract: The S100A6 protein is present in different mammalian cells and tissues including the brain. It binds Ca2+ and Zn2+ and interacts with many target proteins/ligands. The best characterized ligands of S100A6, expressed at high level in the brain, include CacyBP/SIP and Sgt1. Research concerning the functional role of S100A6 and these two ligands indicates that they are involved in various signaling pathways that regulate cell proliferation, differentiation, cytoskeletal organization, and others. In this review, we focused on the expression/localization of these proteins in the brain and on their possible role in neurodegenerative diseases. Published results demonstrate that S100A6, CacyBP/SIP, and Sgt1 are expressed in various brain structures and in the spinal cord and can be found in different cell types including neurons and astrocytes. When it comes to their possible involvement in nervous system pathology, it is evident that their expression/level and/or subcellular localization is changed when compared to normal conditions. Among diseases in which such changes have been observed are Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), epileptogenesis, Parkinson’s disease (PD), Huntington’s disease (HD), and others. Keywords: S100A6; CacyBP/SIP; Sgt1; neurodegeneration; β amyloid plaques; neurofibrillary tangles; Lewy bodies 1. -
Newly Identified Gon4l/Udu-Interacting Proteins
www.nature.com/scientificreports OPEN Newly identifed Gon4l/ Udu‑interacting proteins implicate novel functions Su‑Mei Tsai1, Kuo‑Chang Chu1 & Yun‑Jin Jiang1,2,3,4,5* Mutations of the Gon4l/udu gene in diferent organisms give rise to diverse phenotypes. Although the efects of Gon4l/Udu in transcriptional regulation have been demonstrated, they cannot solely explain the observed characteristics among species. To further understand the function of Gon4l/Udu, we used yeast two‑hybrid (Y2H) screening to identify interacting proteins in zebrafsh and mouse systems, confrmed the interactions by co‑immunoprecipitation assay, and found four novel Gon4l‑interacting proteins: BRCA1 associated protein‑1 (Bap1), DNA methyltransferase 1 (Dnmt1), Tho complex 1 (Thoc1, also known as Tho1 or HPR1), and Cryptochrome circadian regulator 3a (Cry3a). Furthermore, all known Gon4l/Udu‑interacting proteins—as found in this study, in previous reports, and in online resources—were investigated by Phenotype Enrichment Analysis. The most enriched phenotypes identifed include increased embryonic tissue cell apoptosis, embryonic lethality, increased T cell derived lymphoma incidence, decreased cell proliferation, chromosome instability, and abnormal dopamine level, characteristics that largely resemble those observed in reported Gon4l/udu mutant animals. Similar to the expression pattern of udu, those of bap1, dnmt1, thoc1, and cry3a are also found in the brain region and other tissues. Thus, these fndings indicate novel mechanisms of Gon4l/ Udu in regulating CpG methylation, histone expression/modifcation, DNA repair/genomic stability, and RNA binding/processing/export. Gon4l is a nuclear protein conserved among species. Animal models from invertebrates to vertebrates have shown that the protein Gon4-like (Gon4l) is essential for regulating cell proliferation and diferentiation. -
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.