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FLASH GENE
Symbol PMAIP1 contributors: mct/npt/pgu - updated : 05-06-2015
HGNC name phorbol-12-myristate-13-acetate-induced protein 1
HGNC id 9108
Location 18q21.32      Physical location : 57.567.191 - 57.571.538
Synonym name
  • adult T cell leukemia-derived PMA-responsive
  • cellular immediate-early-response protein APR
  • PMA-induced protein 1
  • ATL-derived PMA-responsive gene
  • pro-apoptotic BH3-only protein
  • Synonym symbol(s) APR, NOXA
    DNA
    TYPE functioning gene
    STRUCTURE 4.35 kb     2 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site
    text structure
  • three transcripts, controlled by the same promoter with two TP53 consensus-binding sites, were inducible by TP53
  • promoter contains sites also for E2F-1, Myc, and HIF-1
  • a conserved FOXxO-binding site (DBE; DAF-16 binding element) in the promoter
  • MAPPING cloned Y linked N status provisional
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    2 - 1954 5.8 54 - 2010 20085765
  • exons 1 and 3
  • - - - - 136 - 2008 18630524
  • also called Noxa splicing variant-1 or NSV-1
  • exon-1, partially spliced exon-2, and exon-3
  • is unlikely to play a role in apoptosis regulation
  • - - - - 70 - 2008 18630524
  • also called NSV-2
  • 100p100 identical to the first 70 amino acids of NSV-1
  • is unlikely to play a role in apoptosis regulation
  • EXPRESSION
    Rna function
  • mRNA expression level low in osteoblasts but high in osteoclasts
  • Type
       expressed in (based on citations)
    organ(s)
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Skeletonosteoclast Homo sapiens
    cell lineage
    cell lines adult T-cell leukemia cell line
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • mitochondrial targeting domain (MTD) responsible for inducing fragmentation with two leucine residue playing a key role in the process
  • HOMOLOGY
    interspecies homolog to murine Pmaip1
    Homologene
    FAMILY
  • BH3-only pro-apoptotic Bcl-2 family
  • CATEGORY chaperone/stress
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus
    basic FUNCTION
  • being an essential mediator of TP53-dependent apoptosis
  • important component of the innate immune response of cells to viral infection, leading to enhanced cellular apoptosis that may play a role in limiting viral dissemination
  • with BCL2L11, establish a connection between FKHRL1 and mitochondria, and both BH3-only proteins are critically involved in FKHRL1-induced apoptosis in neuroblastoma
  • may play an important role in the progression of pancreatic cancer
  • suppressor of Myc-induced lymphomagenesis
  • HIF1A-induced proapoptotic gene that mediates hypoxic cell death by generation of ROS
  • promotes activation of caspases and apoptosis
  • promotes mitochondrial membrane changes and efflux of apoptogenic proteins from the mitochondria
  • promotes proteasomal degradation of MCL1
  • competes with BAK1 for binding to MCL1
  • causes mitochondrial fragmentation
  • role in mitochondrial dynamics and cell death
  • having proapoptotic activity and functions downstream of the TP53-mediated apoptotic pathway, to selectively induce apoptosis in tumor cells
  • TP53 transcriptional target involved in the response to DNA-damaging agents
  • participated in triggering mitochondrial dysfunction in multiple apoptotic pathways through distinct mechanisms
  • crucial regulator of osteoclast apoptosis
  • plays a critical role in the regulation of the number of osteoclasts, which may be determined by the level of osteoclast differentiation or survival
  • BIK is a stronger inducer of apoptosis than PMAIP1, and when expressed simultaneously, a combinative effect was observed
  • a function of PMAIP1 was at least in part neutralization of induced myeloid leukemia cell differentiation protein (MCL1) in neutrophils and progenitors
  • apoptosis regulated by BCL2L11- and PMAIP1-driven loss of MCL1 is thus the final step in neutrophil differentiation, required for the termination of neutrophil function and neutrophil-dependent inflammation
  • is involved in the modulation of MCL1 expression
  • triggers the degradation of MCL1 at the mitochondria according to the exclusive location of PMAIP1 at this compartment
  • apoptosis, regulated by PMAIP1, is a critical factor for the selection of high-affinity clones during B cell expansion after antigen triggering
  • sensor of 26S proteasome integrity
  • BCL2L1, and PMAIP1 co-ordinately regulate oxidative stress-induced apoptosis
  • PMAIP1 and, albeit to a lesser extent, BBC3 are essential for DNA damage induced TP63-mediated killing of primordial follicle oocytes
  • PMAIP1 and BBC3 are critical for DNA damage-induced, TP63-mediated oocyte apoptosis
  • important regulator of the number of memory cells formed during infection
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
  • Hippo/MST1-FOXO1-PMAIP1 pathway
  • a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • interacting with MCL1 and BAX
  • strongly upregulated and became associated with both MCL1 and BCL2L11 during apoptosis induced by proteasome inhibition
  • interaction with HRAS (HRAS-induced expression of PMAIP1 and Beclin-1 promotes autophagic cell death) (
  • interacting with HSPA5 (HSPA5 confers resistance to apoptosis induced by BIK and PMAIP)
  • favors the interaction between MCL1 and HUWE1 and consequently affects MCL1 ubiquitination
  • controls HUWE1-dependent MCL1 ubiquitination through the regulation of the MCL1/USP9X interaction
  • PMAIP1 band BBC3 are target genes for TP53
  • TP63 but not TP53 is essential for DNA damage triggered transcriptional induction of BBC3 and PMAIP1 in primordial follicle oocytes
  • TP63 acts via transcriptional induction of the BH3-only proteins, BBC3 and PMAIP1 to cause apoptosis of DNA-damaged primordial follicle oocytes
  • BBC3 like BCL2L11, PMAIP1, is able to act as a direct BAK1 activator
  • BCL2L11 and PMAIP1 are mitochondrial effectors of TAF6delta-driven apoptosis
  • MTD domain of PMAIP1 causes mitochondrial damage by opening mitochondrial permeability transition pore (mPTP) through VDACs, especially VDAC2, during necrotic cell death
  • cell & other
    REGULATION
    activated by MST1, that stimulates transcription of the proapoptotic mediator PMAIP1 in a FOXO1-dependent manner
    induced by highly induced by TNFSF11 during osteoclast maturation
    Other up-regulated by p53
    HRK, BBC3, and PMAIP1 are transcriptionally induced in severe hypoxia and their expression is abrogated by RNA interference against ATF4
    ASSOCIATED DISORDERS
    corresponding disease(s)
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    constitutional       loss of function
    results in an increase in the osteoclast number without affecting osteoclast differentiation and function
    Susceptibility to bleomycin sensitivity (BLM)
    Variant & Polymorphism other
  • genetic variant on 18q21 near the PMAIP1 that is associated with BLM sensitivity
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    osteoarticularbone 
    promising target for suppressing pathological bone destruction
    cancer  
    PMAIP1-triggered BBC3-mediated apoptosis may be a powerful target for cancer therapy, especially early-stage cancer
    ANIMAL & CELL MODELS
  • mice lacking Noxa exhibit a severe osteoporotic phenotype due to an increased number of osteoclasts
  • upon influenza infection Noxa(-/-) mice generate a memory compartment of increased size and clonal diversity
  • Noxa(-/-) mice mount low affinity antibody responses compared with wild-type animals