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MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)

Written2001-03Elizabeth M. Petty, Kenute Myrie
Division of Medical Genetics Departments of Human Genetics, Internal Medicine University of Michigan Medical School 1150 West Medical Center Drive, 4301 MSRB III, Ann Arbor, Michigan 48109-0638, USA

(Note : for Links provided by Atlas : click)

Identity

Alias_namesMAD2 (mitotic arrest deficient
Alias_symbol (synonym)MAD2
HSMAD2
HGNC (Hugo) MAD2L1
LocusID (NCBI) 4085
Atlas_Id 304
Location 4q27  [Link to chromosome band 4q27]
Location_base_pair Starts at 120980579 and ends at 120988013 bp from pter ( according to hg19-Feb_2009)  [Mapping MAD2L1.png]
Local_order As noted on the GM99-GB4 Chromosome 4 map: Position: 548.24 (cR3000) Lod score: 1.16 Reference Interval: D4S2945-D4S430 (115.1-125.1 cM) It is located within the NCBI BAC genomic contig: NT_006302.2 which is part of the homo sapiens chromosome 4 sequence segment
Fusion genes
(updated 2016)
MAD2L1 (4q27) / FAM168B (2q21.1)
Note MAD2L1 was intially (and errounously) mapped by fluorescence in situ hybridization (FISH) to 5q23-q31. Subsequent comprehensive mapping studies using somatic cell hybrid analysis, radiation hybrid (RH) mapping, and FISH localized it to 4q27. This location was susequently confrimed by RH analysis and through the Human Genome Project Draft sequence assembly. A related gene, MAD2L2, maps to to 1p36, and a MAD2 pseudogene maps to to 14q21-q23. Other related family members exist with similar names (eg. MAD2L2, MAD1L1) highlighting the need for using the MAD2L1 nomenclature to avoid confusion (A MAD2L1 pseudogene maps to chromosome 14)

DNA/RNA

 
  Shadded boxes (1-5) depict the 5 exons of MAD2L1. The black triangle indicates a del A mutation that was found in the CAL51 breast cancer cell line. Open triangkes depict the locations of identified sequence variants. Figure is not drawn to scale.
Description the human MAD2L1 DNA sequence had an open reading frame that was 60% identical to the yeast MAD2 gene.
Transcription MAD2L1 has 5 coding exons. No alternative splicing has been described. Regulation of its transcription in human cells is currently poorly understood.

Protein

Description called MAD2A (aliases MAD2-LIKE 1, MD2l, HSMAD2); 205 amino acids; molecular weight: 23,509.95; theoretical pI: 5.02
Expression The MAD2L1 protein is widely expressed in all fetal and adult and fetal tissues studied to date.
Localisation Localizes to the nucleus and associates with unattached kinetochores during after chromosome condensation.
Function
  • Much of what we currently understand about MAD2L1 and its role in the mitotic spindle checkpoint stems from early studies in non-mammalian cells. Several genes have demonstrated critically important, interrelated roles in appropriately responding to aberrant spindle integrity or kinetochore damage by arresting cell cycle progression including BUB (budding uninhibited by benomyl), MAD (mitotic arrest-deficient) genes, additional protein kinase genes, and other cyclin related genes. In budding yeast the mitotic arrest-deficient-2 (MAD2) gene was shown to encode a protein that monitored accurate chromosome segregation via the mitotic spindle checkpoint. The mitotic spindle checkpoint helps regulate cell division to ensure the creation of euploid daughter cells following anaphase and cytokinesis. The checkpoint acts to block cell cycle progression when the mitotic spindle apparatus is not properly assembled or when the kinetochore is not properly attached to the mitotic spindle. The amphibian (Xenopus) homolog of MAD2 was identified and it was demonstrated that the MAD2 protein played a critical role in the normal spindle checkpoint assembly as it associated only with unattached kinetochores in prometaphase and in those cells treated with a microtubule inhibitor, nocodazole. MAD2 was absent from kinetochores in normal cells at metaphase
  • The human homolog of MAD2, MAD2L1, has been isolated through identification of genes that reduced sensitivity to a chemical mitotic spindle assembly inhibiotor, thiabendazole, in yeast that were deficient for a particular kinetochore element , CBF1. The protein encoded by MAD2L1 monitors kinetochore attachments to the mitotic spindle in human cells. Interaction of MAD2L1 and additional checkpoint components with kinetochores unattached to chromosomes blocks the onset of anaphase, preventing missegregation of chromosomes and aneuploidy in resulting daughter cells
  • The nuclear protein encoded by MAD2L1, MAD2A, is a member of the MAD family of proteins that is a critical component of the mitotic checkpoint. MAD2A is required for proper execution of the mitotic checkpoint. When kinetochore-spindle attachment is not completed properly, anaphase is delayed via activation of the mitotic spindle checkpoint. Anaphase is prevented until all chromosomes are properly aligned at the metaphase plate. Normally, the human MAD2A protein localizes as part of a protein complex at unattached kinetochores after chromosome condensation but not after metaphase. Similarly, MAD2A localizes at the kinetochore upon activation of the mitotic spindle checkpoint and mediates cell cycle arrest by associating with CDC20/p55CDC and the anaphase promoting complex (APC) when chromosomes are not properly attached at the kinetochore. Therefore, MAD2A may regulate the activities of the WD40 protein CDC20 that is necessary for progression through anaphase and exit from mitosis. MAD2A reportedly exist in two states, a monomer and a tetramer, both which are capable of binding CDC20. In vitro studies have suggested, but not conclusively established, that only the tetrameric form of MAD2A is capable of inhibiting CDC20 activation of the APC. A yeast 2-hybrid assay using cytoplasmic tails of several a disintegrin and metalloproteinase domain (ADAM) bait proteins, demonstrated that MAD2A interacts strongly with TACE (ADAM17) but not with other ADAMs tested, including ADAM9 which interacts with another MAD family member, the MAD2L2 encoded protein MAD2B. A 35-amino acid stretch of TACE that contains a proline-rich SH3-ligand domain (PXPXXP) has been demonstrated as the interaction site with MAD2A.
  • As noted above, MAD2A is a key protein that functions as part of a larger protein complex that regulates the highly conserved mitotic spindle checkpoint. Appropriate chromosome segregation at anaphase is regulated at least in part by this spindle assembly checkpoint that monitors completion of chromosome-microtubule attachment during metaphase. To further determine the function of Mad2 during normal cell division, Mad2 knockout mice were created and analyzed; day 5.5 embryonic cells lacking Mad2, like mad2 deficient budding yeast cells, grew normally but did not arrest in response to spindle disruption. By d 6.5, the epiblast cells began rapid division associated with widespread chromosome missegregation and subsequent apoptosis. Interestingly, postmitotic trophoblast giant cells survived, however, without Mad2. It was concluded that Mad2 is critical for the spindle assembly checkpoint and accurate chromosome segregation in mitotic mouse cells as well as for embryonic viability, even in the absence of any mitotic spindle damage. Mad2 and the spindle checkpoint in meiosis of S. cerevisiae were further characterized by comparing wildtype and mad2 -/- yeast that lacked normal checkpoint function. In the mad2 deficient yeast cells, meiosis I missegregation was noted to be significantly increased. These studies suggested that mad2 and the spindle checkpoint in budding yeast are critically important for normal meiotic chromosome segregation, despite the fact that normal mad2 function is largely dispensable in wildtype mitosis of budding yeast.
  • Homology
  • Homologous sequences: Mouse: Mm.43444 Mad2l1; Mm.9648 ESTs, Highly similar to AF072933_1 Mad2-like protein [H.sapiens]; Mm.28402 ESTs, Moderately similar to KIAA0280 [H.sapiens]; Rat: Rn.27237 ESTs, Highly similar to AF072933_1 Mad2-like protein; Rn.34733 ESTs, Weakly similar to mitotic checkpoint component Mad2; Drosophila: Dm.LL.40677 CG2948 CG2948 gene product; Dm.LL.38656 CG17498 CG17498 gene product; Human: Hs.19400 MAD2L2
  • Related Proteins: H. sapiens: MAD2L2 (27%); M. musculus: MAD2L1 (95%); D. melanogaster: CG17498 (46%); C. elegans: MDF-2 (53%); S. pombe: Mad2p (48%); Spac12d12.09p (26%); S. cerevisiae: Mad2p (43%) [details]
  • Mutations

    Note No proven germline or somatic disease causing mutations; one somatic frameshift mutation has been identified , due to a 1 bp deletion, in one breast cancer cell line, CAL51, that caused truncation of the resulting protein product as assessed by in vitro transcription and translation assays. The functional significance of this alteration in relationship to cancer needs to be determined

    Implicated in

    Note
    Disease Like other solid tumors, ovarian cancers, especially those at later stages, demonstrate significant aneuploidy and multiple regions of chromosome loss and amplification. MAD2L1 maps to 4q27, an area that is unstable in several cancers as revealed by loss of heterozygosity and comparative genomic hybridization studies. Interestingly, some of the malignant tumors in individuals with BRCA1 germline mutations have somatic loss of chromosome 4q, suggesting that alterations of genes in this region may be associated with breast cancer
    Cytogenetics No cytogenetic translocations involving this gene, however, have been reported or have been associated with any disease, including cancer
    Hybrid/Mutated Gene None described
    Oncogenesis Work by several groups have now suggested that dysfunction of MAD2A may lead to malignancy or degeneration of normal cells, but compelling evidence that supports a role for MAD2L1 alterations in human cancers are still lacking. Despite this lack of solid data, there is increasing suggestive evidence to implicate MAD2L1 alterations in association with the development and/or progression of human cancer. First, aneuploidy is a commonly observed phenotype in many solid tumor malignancies, especially in later stage tumors. Chromosomal instability (CIN) correlates with aneuploidy and is thought to contribute to genetic instability. Thus, it is widely hypothesized that genomic instability which leads to aneuploidy may accelerate malignant progression in many solid tumor malignancies. Mutations in the genes controlling the mitotic checkpoint, including MAD2L1, have therefore been implicated to contribute to CIN in the pathogenesis of solid tumor malignancies. By monitoring proper microtubule assembly and attachment at the kinetochore, the mitotic checkpoint genes regulate the cell cycle to ensure accurate chromosome alignment and segregation at anaphase to generate euploid daughter cells. Loss of appropriate chromosome attachments at the kinetochore or defects in the mitotic spindle lead to cell cycle arrest and a block in the initiation of anaphase. Mad2 is just one member of a handful of yeast genes, the budding uninhibited by benomyl BUB and mitotic arrest deficient (MAD) families of genes, that are important regulators of this mitotic spindle checkpoint. Studies in colorectal cell lines suggest that dominant negative mutations in the human ortholog BUB1 may have a role in CIN and aneuploidy led to speculation about the potential role of MAD2L1 in human cancers. However, no MAD2L1 mutations were identified in colon cancer cells. Human breast tumor cell line T47D has reduced MAD2 expression and it fails to arrest in mitosis after nocodazole treatment. That loss of MAD2 function might also lead to aberrant chromosome segregation in mammalian cells was suggested. A truncation mutation in MAD2L1 in breast cancer with altered protein expression was subsequently reported but no functional studies have yet demonstrated a functional role in oncogenesis has been demonstrated. Studies of Brca2 deficient murine cells further supported a putative role for these genes in cancer as Bub1 mutations were demonstrated to potentiate growth and cellular transformation (Lee et al., 1999). Secondly, the studies of Mad2 knockout mice have demonstrated that embryonic cells lacking Mad2 fail to arrest in response to microtubule inhibitors and that loss of the checkpoint results in chromosome missegregation and apoptosis. It has subsequently been reported that deletion of one allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome missegregation events in the absence of these agents. Furthermore, Mad2 +/- mice develop lung tumors at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.
      

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    Map location and gene structure of the Homo sapiens mitotic arrest deficient 2 (MAD2L1) gene at 4q27.
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    PMID 9615237
     
    Mitotic checkpoint inactivation fosters transformation in cells lacking the breast cancer susceptibility gene, Brca2.
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    PMID 10445022
     
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    Cell. 1991 ; 66 (3) : 519-531.
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    Mitotic forces control a cell-cycle checkpoint.
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    PMID 7854422
     
    Identification of a human mitotic checkpoint gene: hsMAD2.
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    PMID 8824189
     
    MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells.
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    Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells.
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    Citation

    This paper should be referenced as such :
    Petty, EM ; Myrie, K
    MAD2L1 (mitotic arrest deficient 2, yeast, human homolog like-1)
    Atlas Genet Cytogenet Oncol Haematol. 2001;5(2):110-113.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/MAD2L1ID304.html


    External links

    Nomenclature
    HGNC (Hugo)MAD2L1   6763
    Cards
    AtlasMAD2L1ID304
    Entrez_Gene (NCBI)MAD2L1  4085  MAD2 mitotic arrest deficient-like 1 (yeast)
    AliasesHSMAD2; MAD2
    GeneCards (Weizmann)MAD2L1
    Ensembl hg19 (Hinxton)ENSG00000164109 [Gene_View]  chr4:120980579-120988013 [Contig_View]  MAD2L1 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000164109 [Gene_View]  chr4:120980579-120988013 [Contig_View]  MAD2L1 [Vega]
    ICGC DataPortalENSG00000164109
    TCGA cBioPortalMAD2L1
    AceView (NCBI)MAD2L1
    Genatlas (Paris)MAD2L1
    WikiGenes4085
    SOURCE (Princeton)MAD2L1
    Genetics Home Reference (NIH)MAD2L1
    Genomic and cartography
    GoldenPath hg19 (UCSC)MAD2L1  -     chr4:120980579-120988013 -  4q27   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)MAD2L1  -     4q27   [Description]    (hg38-Dec_2013)
    EnsemblMAD2L1 - 4q27 [CytoView hg19]  MAD2L1 - 4q27 [CytoView hg38]
    Mapping of homologs : NCBIMAD2L1 [Mapview hg19]  MAD2L1 [Mapview hg38]
    OMIM601467   
    Gene and transcription
    Genbank (Entrez)AA443733 AF394735 AJ000186 AK223433 AK298228
    RefSeq transcript (Entrez)NM_002358
    RefSeq genomic (Entrez)NC_000004 NC_018915 NT_016354 NW_004929320
    Consensus coding sequences : CCDS (NCBI)MAD2L1
    Cluster EST : UnigeneHs.591697 [ NCBI ]
    CGAP (NCI)Hs.591697
    Alternative Splicing GalleryENSG00000164109
    Gene ExpressionMAD2L1 [ NCBI-GEO ]   MAD2L1 [ EBI - ARRAY_EXPRESS ]   MAD2L1 [ SEEK ]   MAD2L1 [ MEM ]
    Gene Expression Viewer (FireBrowse)MAD2L1 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)4085
    GTEX Portal (Tissue expression)MAD2L1
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ13257   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
    NextProtQ13257  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ13257
    Splice isoforms : SwissVarQ13257
    PhosPhoSitePlusQ13257
    Domaine pattern : Prosite (Expaxy)HORMA (PS50815)   
    Domains : Interpro (EBI)HORMA_dom    Mad2   
    Domain families : Pfam (Sanger)HORMA (PF02301)   
    Domain families : Pfam (NCBI)pfam02301   
    Conserved Domain (NCBI)MAD2L1
    DMDM Disease mutations4085
    Blocks (Seattle)MAD2L1
    PDB (SRS)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    PDB (PDBSum)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    PDB (IMB)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    PDB (RSDB)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    Structural Biology KnowledgeBase1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    SCOP (Structural Classification of Proteins)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    CATH (Classification of proteins structures)1DUJ    1GO4    1KLQ    1S2H    2QYF    2V64    2VFX    3GMH   
    SuperfamilyQ13257
    Human Protein AtlasENSG00000164109
    Peptide AtlasQ13257
    HPRD03274
    IPIIPI00012369   IPI00964981   IPI00877695   
    Protein Interaction databases
    DIP (DOE-UCLA)Q13257
    IntAct (EBI)Q13257
    FunCoupENSG00000164109
    BioGRIDMAD2L1
    STRING (EMBL)MAD2L1
    ZODIACMAD2L1
    Ontologies - Pathways
    QuickGOQ13257
    Ontology : AmiGOmitotic sister chromatid segregation  kinetochore  kinetochore  condensed chromosome kinetochore  spindle pole  protein binding  nucleus  nuclear pore  cytosol  cytosol  sister chromatid cohesion  mitotic cell cycle checkpoint  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process  negative regulation of protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  identical protein binding  protein homodimerization activity  negative regulation of apoptotic process  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of mitotic cell cycle  perinuclear region of cytoplasm  cell division  negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition  negative regulation of APC-Cdc20 complex activity  mitotic spindle  positive regulation of mitotic cell cycle spindle assembly checkpoint  
    Ontology : EGO-EBImitotic sister chromatid segregation  kinetochore  kinetochore  condensed chromosome kinetochore  spindle pole  protein binding  nucleus  nuclear pore  cytosol  cytosol  sister chromatid cohesion  mitotic cell cycle checkpoint  mitotic cell cycle checkpoint  mitotic spindle assembly checkpoint  anaphase-promoting complex-dependent proteasomal ubiquitin-dependent protein catabolic process  negative regulation of protein catabolic process  protein ubiquitination involved in ubiquitin-dependent protein catabolic process  identical protein binding  protein homodimerization activity  negative regulation of apoptotic process  proteasome-mediated ubiquitin-dependent protein catabolic process  negative regulation of mitotic cell cycle  perinuclear region of cytoplasm  cell division  negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle  positive regulation of ubiquitin-protein ligase activity involved in regulation of mitotic cell cycle transition  negative regulation of APC-Cdc20 complex activity  mitotic spindle  positive regulation of mitotic cell cycle spindle assembly checkpoint  
    Pathways : KEGGCell cycle    Oocyte meiosis    Progesterone-mediated oocyte maturation    HTLV-I infection   
    REACTOMEQ13257 [protein]
    REACTOME PathwaysR-HSA-68877 Mitotic Prometaphase [pathway]
    REACTOME PathwaysR-HSA-141405 Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components [pathway]
    REACTOME PathwaysR-HSA-2467813 Separation of Sister Chromatids [pathway]
    REACTOME PathwaysR-HSA-5663220 RHO GTPases Activate Formins [pathway]
    REACTOME PathwaysR-HSA-2500257 Resolution of Sister Chromatid Cohesion [pathway]
    REACTOME PathwaysR-HSA-141430 Inactivation of APC/C via direct inhibition of the APC/C complex [pathway]
    REACTOME PathwaysR-HSA-141444 Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal [pathway]
    REACTOME PathwaysR-HSA-179409 APC-Cdc20 mediated degradation of Nek2A [pathway]
    REACTOME PathwaysR-HSA-176409 APC/C:Cdc20 mediated degradation of mitotic proteins [pathway]
    REACTOME PathwaysR-HSA-141405 Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components [pathway]
    REACTOME PathwaysR-HSA-174184 Cdc20:Phospho-APC/C mediated degradation of Cyclin A [pathway]
    REACTOME PathwaysR-HSA-141430 Inactivation of APC/C via direct inhibition of the APC/C complex [pathway]
    NDEx NetworkMAD2L1
    Atlas of Cancer Signalling NetworkMAD2L1
    Wikipedia pathwaysMAD2L1
    Orthology - Evolution
    OrthoDB4085
    GeneTree (enSembl)ENSG00000164109
    Phylogenetic Trees/Animal Genes : TreeFamMAD2L1
    HOVERGENQ13257
    HOGENOMQ13257
    Homologs : HomoloGeneMAD2L1
    Homology/Alignments : Family Browser (UCSC)MAD2L1
    Gene fusions - Rearrangements
    Polymorphisms : SNP and Copy number variants
    NCBI Variation ViewerMAD2L1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)MAD2L1
    dbVarMAD2L1
    ClinVarMAD2L1
    1000_GenomesMAD2L1 
    Exome Variant ServerMAD2L1
    ExAC (Exome Aggregation Consortium)MAD2L1 (select the gene name)
    Genetic variants : HAPMAP4085
    Genomic Variants (DGV)MAD2L1 [DGVbeta]
    DECIPHER (Syndromes)4:120980579-120988013  ENSG00000164109
    CONAN: Copy Number AnalysisMAD2L1 
    Mutations
    ICGC Data PortalMAD2L1 
    TCGA Data PortalMAD2L1 
    Broad Tumor PortalMAD2L1
    OASIS PortalMAD2L1 [ Somatic mutations - Copy number]
    Somatic Mutations in Cancer : COSMICMAD2L1  [overview]  [genome browser]  [tissue]  [distribution]  
    Mutations and Diseases : HGMDMAD2L1
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    BioMutasearch MAD2L1
    DgiDB (Drug Gene Interaction Database)MAD2L1
    DoCM (Curated mutations)MAD2L1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)MAD2L1 (select a term)
    intoGenMAD2L1
    NCG5 (London)MAD2L1
    Cancer3DMAD2L1(select the gene name)
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
    Diseases
    OMIM601467   
    Orphanet
    MedgenMAD2L1
    Genetic Testing Registry MAD2L1
    NextProtQ13257 [Medical]
    TSGene4085
    GENETestsMAD2L1
    Huge Navigator MAD2L1 [HugePedia]
    snp3D : Map Gene to Disease4085
    BioCentury BCIQMAD2L1
    ClinGenMAD2L1
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD4085
    Chemical/Pharm GKB GenePA30521
    Clinical trialMAD2L1
    Miscellaneous
    canSAR (ICR)MAD2L1 (select the gene name)
    Probes
    Litterature
    PubMed208 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineMAD2L1
    EVEXMAD2L1
    GoPubMedMAD2L1
    iHOPMAD2L1
    REVIEW articlesautomatic search in PubMed
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