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FLASH GENE
Symbol MCL1 contributors: mct/shn - updated : 08-12-2017
HGNC name myeloid cell leukemia sequence 1 (BCL2-related)
HGNC id 6943
EXPRESSION
Type widely
   expressed in (based on citations)
organ(s)
SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
Digestiveliver    
Nervousbrain    
Reproductivemale systemprostate   
Respiratorylung    
Urinarykidney    
tissue
SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
Blood / Hematopoieticbone marrow   
Muscularstriatumskeletal  
cell lineage
cell lines
fluid/secretion
at STAGE
PROTEIN
PHYSICAL PROPERTIES
STRUCTURE
motifs/domains
  • large N-terminal domain containing many motifs that
    • affect its rate of turnover, localisation and phosphorylation status
  • one Bcl-2 homology 1 (BH1) domain
  • one Bcl-2 homology 2 (BH2) domain
  • one Bcl-2 homology 3 (BH3) domain
  • a PEST region rich in putative phosphorylation sites
    • conjugated ubiquitinated
    HOMOLOGY
    interspecies ortholog to Mcl1, Mus musculus
    ortholog to Mcl1, Rattus norvegicus
    ortholog to MCL1, Pan troglodytes
    intraspecies homolog to BCL2
    Homologene
    FAMILY
  • an anti-apoptotic member of the B-cell lymphoma 2 (BCL2) family of proteins
    • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,nuclear envelope
    text
  • localised to various cellular membranes, including
    • the mitochondria and nuclear envelope
    but it also has prominent cytosolic localisation
    basic FUNCTION
  • involved in programmed myeloid cell differentiation
  • involved in programing of differentiation and concomitant maintenance of viability but not of proliferation : isoform 1 inhibits apoptosis while isoform 2 promotes it
  • essential both early in lymphoid development and later on in the maintenance of mature lymphocytes (B and T)
  • essential for preimplantation development and implantation (
  • having an antiapoptotic role in various myeloid neoplasms
  • may control the fate of cells
  • essential modulator of survival during the development and maintenance of a variety of cell lineages
  • blocks the progression of apoptosis by binding and
    • sequestering the pro-apoptotic proteins BCL2 homologous
    antagonist killer (BAK) and BCL2-associated protein X (BAX) which are capable of forming pores in the mitochondrial membrane
  • MCL1 but not BCL2L1 to be indispensable for the formation and persistence of germinal centers (GCs), and B cell memory
  • main anti-apoptotic regulator of activated B cell survival
  • MCL1 and BCL2L1 function in the same apoptotic pathway
  • coordinately regulates apoptosis and autophagy, the outcome being determined by the interplay between BAX and Beclin-1 activation downstream of MCL1 degradation
  • coordinately regulates apoptosis and autophagy in a context-dependent manner
  • combination of BCL2L1 and MCL1 is essential for the viability of the megakaryocyte lineage
    • CELLULAR PROCESS cell cycle, progression
    cell life, antiapoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • Bcl-2-related ovarian killer, Bok (
  • defender against cell death 1, DAD1 (
  • proliferating cell nuclear antigen, PCNA (
  • Bcl-xl/Bcl-2-associated death promoter homolog, BAD
  • Fortilin (
  • Tankyrase 1, TANK1 (
  • BCL2-antagonist/killer, BAK (
  • Immediate early gene X-1, IEX-1 (
  • Mcl-1 ubiquitin ligase E3, Mule (
  • LASU1 (
  • coordinated action of MCL1, IER3, and BCL2L11 controls cell death and survival (new regulatory circuit)
  • Beclin-1 in the mitochondria
  • BAX BH3 domain complexing with the pro-survival proteins MCL1 and BCL2L1
  • PMAIP1 is strongly upregulated and became associated with both MCL1 and BCL2L11 during apoptosis induced by proteasome inhibition
  • SCF(FBW7) (
  • ubiquitin specific peptidase 9, X-linked, USP9X
  • PMAIP1 is involved in the modulation of MCL1 expression
  • PMAIP1 favors the interaction between MCL1 and HUWE1 and consequently affects MCL1 ubiquitination
  • ATG12 directly regulates the apoptotic pathway by binding and inactivating prosurvival BCL2 family members, including BCL2 and MCL1
  • NAA10 positively regulated MCL1 expression, as exogenous NAA10 promoted MCL1 expression, whereas NAA10 silencing decreased MCL1 expression
  • NAA10 inhibits apoptosis through NAA10-RELA-dependent MCL1 transcriptional activation
  • antagonism between MCL1 and BBC3 governs stem/progenitor cell survival during hematopoietic recovery from stress
  • EXOC4 is involved in the regulation of both BCL2 and MCL1 at the mRNA level
  • EXOC3 regulated BCL2 at the mRNA level and the binding affinity of F-box and WD repeat domain containing 7 and MCL1, thereby controlling MCL1 at the protein level
  • ASAH1 plays a critical role in AML survival through regulation of both sphingolipid levels and MCL1
  • mitochondrial fission proteins DNM1L and MFF negatively regulate MARCH5 activity toward MIEF2 and MCL1
  • macrophages confer survival signals via CCR1-dependent translational MCL1 induction in chronic lymphocytic leukemia
  • BCL2 proteins directly promote SUFU turnover, inhibit SUFU-GLI interaction, and induce the expression of the GLI target genes BCL2, MCL1 and BCL2L1
  • MCL1 is an upstream stress-sensitive protein, functional in AMBRA1-mediated mitophagy
  • MCL1 stability is regulated by the kinase GSK3B and the E3 ubiquitin ligase HUWE1 in regulating AMBRA1-mediated mitophagy
    • cell & other
    REGULATION
    Other MCL1 degradation can occur independently of ubiquitinylation
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --over  
    in NPM-ALK positive anaplastic large cells lymphoma
    tumoral     --over  
    in rhabdomyosarcoma
    tumoral     --over  
    in severalhaematological cancers and solid tumours, including chronic myeloid leukemia and hepatocellular carcinoma
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhemopathy 
    attractive target and survival factor in neoplastic mast cells in systemic mastocytosis
    cancer  
    attractive and potential therapeutic target in a number of malignancies
    cancerhemopathy 
    potential target in germinal center-derived lymphomas that do not overexpress BCL2L1
    ANIMAL & CELL MODELS
  • Deletion of Mcl-1 resulted in peri-implantation embryonic lethality in mouse (
  • mice conditional for Mcl-1 display a profound reduction in B and T lymphocytes when MCL-1 is removed, deletion of Mcl-1 during early lymphocyte differentiation increased apoptosis and arrested the development at pro-B-cell and double-negative T-cell stages (
  • deletion of Mcl-1 in cortical neurons of transgenic mice activates a robust autophagic response