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FLASH GENE
Symbol MAD1L1 contributors: npt/mct/pgu - updated : 25-01-2016
HGNC name MAD1 mitotic arrest deficient-like 1 (yeast)
HGNC id 6762
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • two highly conserved domains, Sin3-interacting domain (SID)
  • and basic helix-loop-helix leucine zipper domain (bHLHzip), which are essential for the function during molecular switching from proliferation to differentiation
  • C-terminal domain is a part of an extensive kinetochore-binding interface of MAD1L1, and rationalize graded kinetochore targeting of MAD1L1 during checkpoint signaling
    • mono polymer homomer , dimer
    HOMOLOGY
    interspecies homolog to yeast (mitotic arrest deficient) MADH1
    Homologene
    FAMILY
  • ezrin-radixin-moesin family
  • MAD1 family
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton,microtubule,centrosome
    intracellular,cytoplasm,cytoskeleton,microtubule,mitotic spindle
    intracellular,nucleus,chromatin/chromosome,centromere
    intracellular,nucleus,chromatin/chromosome,kinetochore
    text
  • associated with microtubule-unattached kinetochores in mitotic cells and is a component of the spindle assembly checkpoint (SAC)
  • localise to kinetochores with BUB1B and MAD2L1
  • kinetochore localization of MAD1L1 is sufficient for a metaphase arrest that depends on MAD1L1-MAD2L1 binding
    • basic FUNCTION
  • preventing the onset of anaphase until all chromosomes are properly aligned at the metaphase plate
  • playing a role in mitotic checkpoint
  • acting in a surveillance mechanism that mediates a metaphase delay in response to nonexchange chromosomes
  • involved in cell growth control and inhibition of entry into S phase until late G1
  • playing a complex role in the development of small-cell lung cancer as well as other tumors
  • required for MAD2L1 localization to kinetochores and the association of MAD2L1 with the kinetochore is a pre-requisite for its SAC functionb
  • Myc antagonist, upstream regulator of MAD2L1, that forms a tight core complex with MAD2L1 and facilitates MAD2L1 binding to Cdc20
  • plays an important role in proper mitotic progression
  • IK is a spindle pole-associated protein that colocalizes with MAD1L1 at the spindle poles in metaphase and anaphase
  • its overexpression causes aneuploidy and chromosomal instability through weakening mitotic checkpoint signaling caused by mislocalization of the MAD1L1 binding partner MAD2L1
  • MAD2L1 is one of the key components of the spindle and mitotic checkpoint complex that regulates the fidelity of cell division along with MAD1L1, CDC20, BUB1B
    • CELLULAR PROCESS cell cycle, checkpoint
    cell life, differentiation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • essential component of the mitotic spindle assembly checkpoint
  • component of the SAC and form an heterodimer with MAD2L1 at the nuclear pore complex as a cell enters mitosis
    • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting as an homodimer with MAD2L1
  • associating and inactivating the anaphase promoting complex (APC)
  • interaction of NUP153 with the spindle assembly checkpoint protein MAD1L1 is important in the regulation of the spindle checkpoint
  • interacting with MAD2L1 (recruitment of the spindle-assembly checkpoint protein MAD2L1, through MAD1L1, to non-bioriented kinetochores is needed to stop cell-cycle progression)
  • binds to the CDH1 promoter region (regulates the expression of CDH1 and prevents cell migration)
  • CNOT3 negatively regulates the expression of MAD1L1, which is evidenced by the stabilization of MAD1L1 mRNA upon CNOT3 depletion
  • IK interacts with the human SAC protein MAD1L1
  • unexpected connection of NUP107 with the mitotic spindle assembly checkpoint protein MAD1L1
  • TPR is required for normal SAC response by stabilizing MAD1L1 and MAD2L2 before mitosis
  • MAD1L1 plays a minor role in influencing the MAD2L1-dependent regulation of AURKB suggesting that the effects of MAD2L1 on AURKB are independent of the spindle checkpoint complex
  • LMO7 interacted with the spindle assembly checkpoint (SAC) protein MAD1L1
    • cell & other
    REGULATION
    activated by TP53 gain of function mutant
    Other hyperphosphorylated when PLK1 is overexpressed and that the kinase activity of PLK1 is required for MAD1L1 to locate to microtubule-unattached kinetochores
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral somatic mutation      
    in lung cancer and colon cancer
    tumoral     --low  
    in lung cancer and colon cancer
    tumoral   LOH    
    in breast cancer
    tumoral somatic mutation      
    in acute leukaemia
    constitutional     --over  
    its up-regulation may promote tumors and cause resistance to current therapies
    Susceptibility to lung cancer
    Variant & Polymorphism other genetic variants in MAD1L1 confer susceptibility to lung cancer, which might result from reduced spindle checkpoint function due to attenuated function of MAD1L1
    Candidate gene
    Marker
  • reduced MAD1L1 expression is a new potential diagnostic symptom of tumor metastasis
    • Therapy target
    ANIMAL & CELL MODELS