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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
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