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Category   Symbol Source: HGNC EntrezGene Ensembl GeneCards RNA genes CroW21
GIFtS

SUMO4 Gene

protein-coding   GIFtS: 54
GCID: GC06P149763

SMT3 suppressor of mif two 3 homolog 4 (S. cerevisiae)

(Previous name: SMT3 suppressor of mif two 3 homolog 4 (yeast) )
(Previous symbol: SMT3H4)
 Explore 14 diseases affiliated with
SUMO4 via our new
 Human Malady Compendium 
Biological research products
for SUMO4
    

(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, and/or 10fRNAdb)
About This Section

Aliases
SMT3 Suppressor Of Mif Two 3 Homolog 4 (S. Cerevisiae)1 2     SMT3 Suppressor Of Mif Two 3 Homolog 4 (Yeast)1
SMT3H41 2 3     Small Ubiquitin-Like Modifier 4 Protein2
DJ281H8.41     Small Ubiquitin-Related Modifier 42
SUMO-42 3     SMT3 Suppressor Of Mif Two 3 Homolog 22
IDDM52 5     Small Ubiquitin-Like Protein 43

External Ids:    HGNC: 211811   Entrez Gene: 3870822   Ensembl: ENSG000001776887   OMIM: 6088295   UniProtKB: Q6EEV63   

Export aliases for SUMO4 gene to outside databases

Previous GC identifers: GC06U900642 GC0XM114776 GC06P147288


(According to Entrez Gene, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
About This Section

Entrez Gene summary for SUMO4:
This gene is a member of the SUMO gene family. This family of genes encode small ubiquitin-related modifiers that are
attached to proteins and control the target proteins' subcellular localization, stability, or activity. The protein
described in this record is located in the cytoplasm and specifically modifies IKBA, leading to negative regulation of
NF-kappa-B-dependent transcription of the IL12B gene. A specific polymorphism in this SUMO gene, which leads to the
M55V substitution, has been associated with type I diabetes. The RefSeq contains this polymorphism. (provided by
RefSeq, Jul 2008)

UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6
Function: Ubiquitin-like protein which can be covalently attached to target lysines as a monomer. Does not seem to be
involved in protein degradation and may modulate protein subcellular localization, stability or activity. Upon
oxidative stress, conjugates to various anti-oxidant enzymes, chaperones, and stress defense proteins. May also
conjugate to NFKBIA, TFAP2A and FOS, negatively regulating their transcriptional activity, and to NR3C1, positively
regulating its transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1
complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I

Gene Wiki entry for SUMO4


(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 69), Regulatory elements and Epigenetics data according to QIAGEN, SABiosciences, and/or SwitchGear Genomics)
About This Section
RefSeq DNA sequence:
NC_000006.11  NC_018917.1  NT_025741.15  
Regulatory elements:
   SABiosciences Regulatory transcription factor binding sites in the SUMO4 gene promoter:
         GR   AP-2alpha isoform 3   AML1a   AP-2alpha isoform 2   GATA-1   PPAR-alpha   GR-alpha   AP-2alpha isoform 4   AP-2alpha   AP-2alphaA   
         Other transcription factors

Browse SwitchGear Promoter luciferase reporter plasmids
   Search SABiosciences Chromatin IP Primers for SUMO4

Epigenetics:
QIAGEN PyroMark CpG Assay predesigned Pyrosequencing DNA Methylation assays in human, mouse, rat SUMO4


Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 6q25   Ensembl cytogenetic band:  6q25.1   HGNC cytogenetic band: 6q25.1

SUMO4 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
SUMO4 gene location

GeneLoc information about chromosome 6         GeneLoc Exon Structure

GeneLoc location for GC06P149763:  view genomic region     (about GC identifiers)

Start:
149,721,495 bp from pter      End:
149,722,182 bp from pter
Size:
688 bases      Orientation:
plus strand

(According to 1UniProtKB, HORDE, neXtProt, Ensembl, and/or Reactome, Modification sites according to 2PhosphoSitePlus, Specific Peptides from DME, Protein expression images according to data from SPIRE MOPED and PaxDb, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Uscn,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Uscn, Ontologies according to Gene Ontology Consortium 01 Mar 2013 and Entrez Gene, Antibodies by EMD Millipore, R&D Systems, GenScript, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, Abcam, and/or Uscn)
About This Section

UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6 (See protein sequence)
Recommended Name: Small ubiquitin-related modifier 4 precursor  
Size: 95 amino acids; 10685 Da
Subunit: Interacts with SAE2. Covalently attached to a number of proteins (Probable)
Secondary accessions: A1L3W5

Explore the universe of human proteins at neXtProt for SUMO4: NX_Q6EEV6

Post-translational modifications:

  • In contrast to SUMO1, SUMO2 and SUMO3, seems to be insensitive to sentrin-specific proteases due to the presence of
  • Pro-90. This may impair processing to mature form and conjugation to substrates1
  • View modification sites using PhosphoSitePlus2
  • View neXtProt modification sites for NX_Q6EEV6

  • SUMO4 Protein expression data from MOPED and PaxDb:    About this image 
    Estimated protein expression log10 (pmol).

    REFSEQ proteins: NP_001002255.1  
    ENSEMBL proteins: 
     ENSP00000318635  

    Human Recombinant Protein Products: 
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    Uscn Proteins for SUMO4


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    (According to InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
    About This Section

    SUMO4 for domains           About GeneDecksing

    4 InterPro domains/families:
     IPR022617 SUMO
     IPR027218 SUMO_chordates
     IPR000626 Ubiquitin
     IPR019955 Ubiquitin_supergroup

    Graphical View of Domain Structure for InterPro Entry Q6EEV6

    ProtoNet protein and cluster: Q6EEV6

    1 Blocks protein family: IPB000626 Ubiquitin domain

    UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6
    Similarity: Belongs to the ubiquitin family. SUMO subfamily
    Similarity: Contains 1 ubiquitin-like domain


    (According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013,
    bound targets from SABiosciences, miRNA Gene Targets from miRTarBase shRNA from OriGene, RNAi from EMD Millipore, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, SwitchGear Genomics, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, LifeMap BioReagents, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene.)
    About This Section

    Function Summary:

         UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6
    Function: Ubiquitin-like protein which can be covalently attached to target lysines as a monomer. Does not seem to be
    involved in protein degradation and may modulate protein subcellular localization, stability or activity. Upon
    oxidative stress, conjugates to various anti-oxidant enzymes, chaperones, and stress defense proteins. May also
    conjugate to NFKBIA, TFAP2A and FOS, negatively regulating their transcriptional activity, and to NR3C1, positively
    regulating its transcriptional activity. Covalent attachment to its substrates requires prior activation by the E1
    complex SAE1-SAE2 and linkage to the E2 enzyme UBE2I

    miRNA
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    Inhib. RNA
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    Search Advanced Cell Diagnostics for RNAscope RNA in situ hybridization assays for SUMO4

    Gene Ontology (GO): 1 molecular function term (GO ID links to tree view):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0019789SUMO ligase activity IEA--


    SUMO4 for ontologies           About GeneDecksing


    2 GenomeRNAi human phenotypes for SUMO4:
     Decreased BPV1 E2 protein expr  Increased HPV18 LCR reporter a 


    (Pathways according to EMD Millipore, R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to SABiosciences, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Mar 2013 via Entrez Gene).
    About This Section

    Unified GeneCards pathways  About this table 
    See pathways by source

    Super-pathwaycontained gene-specific pathways
    1RNA transport
    RNA transport1.00

    Pathway sources
    See GeneCards unified pathways
    Show all pathways



    1         Kegg Pathway  (Kegg details for SUMO4):
        RNA transport


    SUMO4 for pathways           About GeneDecksing

    Interactions:

        SABiosciences Gene Network CentralTM Interacting Genes and Proteins Network for SUMO4

    STRING Interaction Network Preview (showing 5 interactants - click image to see 25)

    5/108 Interacting proteins for SUMO4 (Q6EEV63 ENSP000003186354) via UniProtKB, MINT, STRING, and/or I2D (see all 108)
    InteractantInteraction Details
    GeneCardExternal ID(s)
    HSPA1AP081073, ENSP000003648024I2D: score=1 STRING: ENSP00000364802
    ACADMP113103, ENSP000004096124I2D: score=1 STRING: ENSP00000409612
    ATP5BP065763, ENSP000002620304I2D: score=1 STRING: ENSP00000262030
    CALRP277973, ENSP000003208664I2D: score=1 STRING: ENSP00000320866
    CCT7Q998323, ENSP000002580914I2D: score=1 STRING: ENSP00000258091
    About this table

    Gene Ontology (GO): 2 biological process terms (GO ID links to tree view):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0016925protein sumoylation IEA--
    GO:0045944positive regulation of transcription from RNA polymerase II promoter IEA--


    SUMO4 for ontologies           About GeneDecksing



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience HMDB, BitterDB, and/or Novoseek, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB, with drugs/clinical trials/news search links to CenterWatch)
    About This Section

    SUMO4 for compounds           About GeneDecksing

    Browse Small Molecules at EMD Millipore
    Browse drugs & compounds from Enzo Life Sciences

    Browse Tocris compounds for SUMO4
    2 Novoseek chemical compound relationships for SUMO4 gene    About this table
    Compound   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    valine 36.4 4 15730420 (3), 15123604 (1)
    methionine 24.2 2 15730420 (1), 15123604 (1)

    Search CenterWatch for drugs/clinical trials and news about SUMO4 

    (Secondary structures according to fRNAdb,
    GenBank/EMBL/DDBJ Accessions according to
    Unigene (Build 235 Homo sapiens; Mar 10 2013) or GenBank,
    RefSeq according to Entrez Gene,
    DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
    exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
    RNAi Products from EMD Millipore,
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    Tagged/untagged cDNA clones from OriGene, SwitchGear Genomics, GenScript, DNA2.0, Vector BioLabs, Primers from OriGene, SABiosciences, and/or QIAGEN )
    About This Section

    REFSEQ mRNAs for SUMO4 gene: 
    NM_001002255.1  

    Unigene Cluster for SUMO4:

    SMT3 suppressor of mif two 3 homolog 4 (S. cerevisiae)
    Hs.657168  [show with all ESTs]
    Unigene Representative Sequence: AY340238
    1 Ensembl transcript including schematic representation, and UCSC links where relevant:
    ENST00000326669(uc003qml.3)

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    Additional cDNA sequence: 

    AY340238.1 BC130305.1 

    1 DOTS entry:

    DT.91998796 

    GeneLoc Exon Structure


    (RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, plus additional links to Genevestigator, and/or SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from SABiosciences, Primers from OriGene, SABiosciences, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
    About This Section

    SUMO4 expression in normal human tissues (normalized intensities)
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS
    CGAP TAG: AAGTAACTGG

    Microarray
    RNAseq (Illumina Body Map)
    (100×FPKM)½
    SAGE (Serial Analysis of Gene Expression)

    About this image
    See SUMO4 Protein Expression from SPIRE MOPED and PaxDB
    Genevestigator expression for SUMO4

    SOURCE GeneReport for Unigene cluster: Hs.657168

    UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6
    Tissue specificity: Expressed mainly in adult and embryonic kidney. Expressed at various levels in immune tissues, with
    the highest expression in the lymph node and spleen

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    In Situ
    Assay Products:
     

     
    Search Advanced Cell Diagnostics for RNAscope RNA in situ hybridization assays for SUMO4

    (Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
    About This Section

    This gene was present in the common ancestor of eukaryotes.

    Orthologs for SUMO4 gene from 6/19 species (see all 19)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    chicken
    (Gallus gallus)
    Aves SUMO2_CHICK6
    Small ubiquitin-related modifier 2
    85(a)
    1 → many
    18(10640127-10646733)
    lizard
    (Anolis carolinensis)
    Reptilia --
    --
    85(a)
    1 → many
    2(114742718-114750546)
    zebrafish
    (Danio rerio)
    Actinopterygii sumo2a6
    sumo2b6
    SMT3 suppressor of mif two 3 homolog 2b
    61(a)
    50(a)
    possible ortholog
    possible ortholog
    6(18686358-18692065)
    3(6945637-6963988)
    fruit fly
    (Drosophila melanogaster)
    Insecta smt36
    smt3
    60(a)
    1 → many
    2L(6966780-6967644)
    thale cress
    (Arabidopsis thaliana)
    eudicotyledons SUM16
    SUMO 26
    (see all 7)
    small ubiquitin-related modifier 2
    (see all 7)
    42(a)
    37(a)
    (see all 7)
    many ↔ many
    many ↔ many
    (see all 7)
    4(13497326-13498730)
    5(22383560-22384925)
    rice
    (Oryza sativa)
    Liliopsida --
    --
    ubiquitin family domain containing protein, expres...
    ubiquitin family domain containing protein, expres...
    44(a)
    43(a)
    many ↔ many
    many ↔ many
    1(40063602-40065230)
    1(40060804-40062480)


    ENSEMBL Gene Tree for SUMO4 (if available)
    TreeFam Gene Tree for SUMO4 (if available) 

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
    About This Section
    Paralogs for SUMO4 gene
    SUMO22  ENSG000002285322  SUMO12  SUMO32  
    4 SIMAP similar genes for SUMO4 using alignment to 1 protein entry:     SUMO4_HUMAN:
    SUMO2    SUMO3    NFATC2IP    SUMO1

    SUMO4 for paralogs           About GeneDecksing



    (SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD) and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers from QIAGEN, Cancer Mutation PCR Arrays and Assays and Copy Number PCR Arrays from SABiosciences)
    About This Section

    UniProtKB/Swiss-Prot: SUMO4_HUMAN, Q6EEV6
    Polymorphism: Variant Val-55 could be associated with insulin-dependent diabetes mellitus 5 (IDDM5) [MIM:600320]


    Human Gene Mutation Database (HGMD): SUMO4

    SABiosciences Cancer Mutation PCR Assays
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    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Novoseek, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
    About This Section

    SUMO4 for disorders           About GeneDecksing

    OMIM gene information: 608829   
    OMIM disorders: 600320  
    14 diseases for SUMO4:    About MalaCards
    diabetes mellitus, insulin-dependent, 5    diabetes mellitus    type 2 diabetes mellitus    systemic lupus erythematosus
    lupus erythematosus    coronary heart disease    rheumatoid arthritis    diabetic retinopathy
    behcet's disease    graves' disease    nephropathy    arthritis
    psoriasis    malaria

    1 disease from the University of Copenhagen DISEASES database for SUMO4:
    Diabetes mellitus

    7 Novoseek disease relationships for SUMO4 gene    About this table

    Disease   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    autoimmune thyroid disease 62.7 1 16735488 (1)
    diabetes autoimmune 53.2 1 16735488 (1)
    autoimmunity 50.7 1 17374705 (1)
    diabetes mellitus insulin-dependent 46.9 4 15730420 (1), 15123604 (1), 17130563 (1)
    autoimmune diseases 46.3 5 16735488 (2), 17459725 (1), 19956095 (1), 16821265 (1)
    genetic susceptibility 40.5 1 16735488 (1)
    rheumatoid arthritis 21.2 4 16821265 (2), 16735488 (1), 16159953 (1)

    Genetic Association Database (GAD): SUMO4
    Human Genome Epidemiology (HuGE) Navigator: SUMO4 (30 documents)

    Export disorders for SUMO4 gene to outside databases

    (in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
    About This Section

    PubMed articles for SUMO4 gene, integrated from 9 sources (see all 62):
    (articles sorted by number of sources associating them with SUMO4)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. A M55V polymorphism in a novel SUMO gene (SUMO-4) differentially activates heat shock transcription factors and is associated with susceptibility to type I diabetes mellitus. (PubMed id 15123604)1, 2, 3, 4, 9 Bohren K.M.... Owerbach D. (2004)
    2. A functional variant of SUMO4, a new I kappa B alpha modifier, is associated with type 1 diabetes. (PubMed id 15247916)1, 2, 4, 9 Guo D.... Wang C.-Y. (2004)
    3. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. (PubMed id 15678135)1, 2, 4 Qu H.... Polychronakos C. (2005)
    4. The type 1 diabetes susceptibility gene SUMO4 at IDDM5 is not associated with susceptibility to rheumatoid arthritis or juvenile idiopathic arthritis. (PubMed id 16159953)1, 4, 9 Gibbons L.J....Hinks A. (2005)
    5. No association of the codon 55 methionine to valine polymorphism in the SUMO4 gene with Graves' disease. (PubMed id 15730420)1, 4, 9 Jennings C.E....Pearce S.H. (2005)
    6. Study of the role of functional variants of SLC22A4, RUNX1 and SUMO4 in systemic lupus erythematosus. (PubMed id 16249223)1, 4 Orozco G....Martin J. (2006)
    7. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. (PubMed id 15678134)1, 2 Smyth D.J.... Todd J.A. (2005)
    8. Proteomic analysis of SUMO4 substrates in HEK293 cells under serum starvation-induced stress. (PubMed id 16236267)1, 2 Guo D.... Wang C.-Y. (2005)
    9. A proline-90 residue unique to SUMO-4 prevents maturation and sumoylation. (PubMed id 16198310)1, 2 Owerbach D.... Bohren K.M. (2005)
    10. Assessing the validity of the association between the SUMO4 M55V variant and risk of type 1 diabetes. (PubMed id 15678137)1, 2 Park Y.... Kim D. (2005)

    (in PubMed, OMIM, and NCBI Bookshelf)
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    (According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
    About This Section
    Entrez Gene: 387082 HGNC: 21181 Ensembl:ENSG00000177688 euGenes: HUgn387082 ECgene: SUMO4 Kegg: 387082
    H-InvDB: SUMO4

    (According to HUGE)
    About This Section
      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL,
    Wikipedia and/or GeneReviews via UniProtKB/Swiss-Prot)
    About This Section
    NameDescription
    PharmGKB entry for SUMO4 Pharmacogenomics, SNPs, Pathways
    Wikipedia http://en.wikipedia.org/wiki/SUMO_protein

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
    About This Section
    Patent Information for SUMO4 gene:
    Search GeneIP for patents involving SUMO4

    GeneCards and IP:
    Japan Patent Office Licenses GeneCards     European Patent Office Licenses GeneCards     Improving the IP Search



    (Antibodies, recombinant proteins, and assays from EMD Millipore, R&D Systems, OriGene, QIAGEN, GenScript, Cell Signaling Technology, SABiosciences, Novus Biologicals, Sino Biological, Enzo Life Sciences, Abcam, ProSpec, Uscn, Thermo Fisher Scientific, Gene Editing from DNA2.0, Clones from EMD Millipore, OriGene, GenScript, Sino Biological, DNA2.0, SwitchGear Genomics, Vector BioLabs, Cell lines from GenScript and LifeMap BioReagents, PCR Arrays from SABiosciences, Drugs and/or compounds from EMD Millipore, Tocris Bioscience, and/or Enzo Life Sciences),
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