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FLASH GENE
Symbol PML contributors: shn - updated : 21-05-2013
HGNC name promyelocytic leukemia
HGNC id 9113
Corresponding disease
PML acute promyelocytic leukemia (APL)
Location 15q24.1      Physical location : 74.287.013 - 74.340.153
Synonym name
  • tripartite motif protein TRIM19
  • promyelocytic leukemia, inducer of
  • RING finger protein 71
    • Synonym symbol(s) MYL, TRIM19, PP8675, RNF71
    DNA
    TYPE functioning gene
    SPECIAL FEATURE
    text a megabase-scale insertion/deletion polymorphism 3' to PML (see GLP)
    STRUCTURE 53.14 kb     9 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence cytosine-phosphate-guanine/HTF
    Binding site   HRE
    text structure
  • flanked by two CpG islands
  • interferon stimulated response element and GAS motif in the 5'utr
    • MAPPING cloned Y linked N status confirmed
    Map cen - D15S215 - D15S1026 - PML PML - D15S160 - D15S965 - qter
    Physical map
    NEO1 15q22.3-q23 neogenin homolog 1 (chicken) LOC388134 15 LOC388134 HCN4 15q24-q25 hyperpolarization activated cyclic nucleotide-gated potassium channel 4 LOC283677 15q22.33 hypothetical LOC283677 MRPS15P1 15q22 hypothetical LOC283677 SDFR1 15q22 stromal cell derived factor receptor 1 B7H3 15q23-q24 B7 homolog 3 LOC388135 15 similar to RIKEN cDNA 6030419C18 gene MGC34741 15q22.33 hypothetical protein MGC34741 LOXL1 15q22 lysyl oxidase-like 1 STOML1 15q22 stomatin (EPB72)-like 1 PML 15q22 promyelocytic leukemia LOC390604 15 similar to Dynamin-1 (D100) (Dynamin, brain) (B-dynamin) LOC342096 15q22.33 similar to Golgi autoantigen, golgin subfamily A member 6 (Golgin linked to PML) (Golgin-like protein) KIAA1465 15q22.33 KIAA1465 protein ISLR 15q23-q24 immunoglobulin superfamily containing leucine-rich repeat FLJ12541 15q22.33 stimulated by retinoic acid gene 6 LOC338951 15q22.33 hypothetical LOC338951 FLJ32855 15q23 hypothetical protein FLJ32855 CYP11A1 15q23-q24 cytochrome P450, family 11, subfamily A, polypeptide 1 SEMA7A 15q22.3-q23 sema domain, immunoglobulin domain (Ig), and GPI membrane anchor, (semaphorin) 7A MGC14421 DRIL2 15q24 sema domain, immunoglobulin domain (Ig), and GPI membrane anchor, (semaphorin) 7A CLK3 15q24 CDC-like kinase 3 FLJ21128 15q23 hypothetical protein FLJ21128 CYP1A1 15q22-q24 cytochrome P450, family 1, subfamily A, polypeptide 1 CYP1A2 15q22-q24 cytochrome P450, family 1, subfamily A, polypeptide 2 CSK 15q23-q25 c-src tyrosine kinase LMAN1L 15q22-23 lectin, mannose-binding, 1 like DKFZP434C131 15q23 DKFZP434C131 protein SCAMP2 15q23-q25 secretory carrier membrane protein 2 MPI 15q22-qter mannose phosphate isomerase FLJ00005 COX5A 15q25 cytochrome c oxidase subunit Va Rpp25 15q23 RNase P protein subunit p25
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    9 splicing 5600 97.4 882 nuclear PML isoform 2011 21115099
    also called variant alpha
    7 splicing 3751 67.3 611 nuclear PML isoform 2011 21115099
  • also called variant beta
  • different 3'UTR and 3' coding region compared to variant 1
    • 8 splicing 3096 61.9 560 nuclear PML isoform 2011 21115099
  • also called variant epsilon
  • different 3'UTR and 3' coding region compared to variant 1
    • 8 splicing 2254 69.9 633 nuclear PML isoform 2011 21115099
  • also called variant zeta
  • different 3'UTR and 3' coding region compared to variant 1
    • 6 splicing 1851 47.4 423 nuclear PML isoform 2011 21115099
  • variant eta
  • multiple differences in the coding region compared to variant 1 which results in a translational frameshift
    • 5 splicing 1797 48.5 435 nuclear PML isoform 2011 21115099
  • also called variant theta
  • multiple differences in the coding region compared to variant 1 which results in a translational frameshift
    • 8 splicing 3088 90.6 829 - 2011 21115099
    D. variant kappa
  • different 3'UTR and 3' coding region compared to variant 1
    • 7 splicing 2110 64.9 585 - 2011 21115099
  • variant lambda
  • multiple differences in the coding region compared to variant 1 which results in a translational frameshift
    • 7 splicing 2944 85.6 781 - 2011 21115099
  • also called variant 11
  • multiple differences in the coding region compared to variant 1 which results in a translational frameshift
    		•
    EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestiveintestinelarge intestinecolon moderately
     pancreas exocrine   highly
    Lymphoid/Immunelymph node   highly
    Reproductivefemale systemuterus  highly
     female systemovary  predominantly
     female systembreastmammary gland moderately
     male systemprostate  moderately
    Respiratorylung   moderately
    Skin/Tegumentskin   moderately
    Urinarybladder   highly
     kidney   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Nervousperipherous   
    cell lineage restricted to neural progenitor cells (NPCs) in the developing neocortex of the mouse
    cell lines
    fluid/secretion blood
    at STAGE
    cell cycle     cell cycle, G1, S, G2, M
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • an N-terminal RING zinc finger domain
  • two B boxes (a B-box type 1 and a B-box type 2)
  • a leucine coiled-coil domain
  • a RBCC/TRIM motif comprising several cysteine-rich zinc-binding domains (RING and B-boxes) and a coiled-coil domain
  • a nuclear localization signal (NLS)
    • conjugated PhosphoP , Other
    mono polymer homomer , dimer , complex
    HOMOLOGY
    interspecies ortholog to Pml, Rattus norvegicus
    ortholog to PML, Pan troglodytes
    Homologene
    FAMILY
  • B box family, RBCC (TRIM family)
  • member of the tripartite motif (TRIM) family
  • C-V TRIM family
    • CATEGORY transcription factor
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,organelle,mitochondria
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,cytosolic
    intracellular,nucleus,nucleoplasm,nuclear bodies
    intracellular,nucleus,chromatin/chromosome,centromere
    intracellular,nucleus,nucleolus
    text
  • extranuclear Pml was specifically enriched at the endoplasmic reticulum (ER) and at the mitochondria-associated membranes, signaling domains involved in ER-to-mitochondria calcium ion (Ca2+) transport and in induction of apoptosis
    • basic FUNCTION
  • recruiting the nuclear corepressor histone deacetylase complex, essential for multiple apoptotic pathways in early hematopoiesis and late erythropoiesis
  • acting as a putative controller of genes devoted to MHC class I antigen presentation
  • mediating the interferon induced antiviral state against a complex retrovirus (foamy virus, via its association with the viral transactivator)
  • may play an important role in recruitment of ELF4 into PML nuclear bodies
  • acting as a critical inhibitor of neoangiogenesis in both ischaemic and neoplastic conditions, through the control of protein translation
  • negatively regulating the synthesis rate of hypoxia-inducible factor 1alpha (HIF-1alpha) by repressing mammalian target of rapamycin (mTOR)
  • cytoplasmic Pml is an essential modulator of TGF-beta signaling
  • plays an important role in cell growth and survival
  • role of PML/Nur77 interaction in regulating cell growth and apoptosis
  • role for PML in the regulation of TP53 by CSNK1A1
  • central regulator of cell proliferation and apoptosis
  • role in controlling the function of neural progenitor cells in the central nervous system
  • regulates the size of the cerebral cortex
  • broadly regulate the early (and transcription independent) apoptotic response, and regulates apoptosis at endoplasmic reticulum by modulating calcium release
  • PML and the key Wnt signaling regulator AXIN1 regulate TP53-dependent apoptosis in response to DNA damage
  • physiological role of PML in apoptosis
  • functions as a positive regulator of IFNG signaling
  • through its scaffold properties is able to control cell growth and survival at many different levels (
  • exerts its essential role in hematopoietic stem cell maintenance through regulation of PPAR signaling and fatty-acid oxidation
  • selectively associate with transcriptionally active genomic regions, including the gene-rich major histocompatibility (MHC) locus
  • is a coregulator of IFNG-induced MHC class II expression
    • CELLULAR PROCESS cell life, differentiation
    cell life, proliferation/growth
    cell life, cell death/apoptosis
    nucleotide, repair, recombination
    nucleotide, transcription, regulation
    protein, ubiquitin dependent proteolysis
    PHYSIOLOGICAL PROCESS development
    text
  • negative regulation of cell proliferation and angiogenesis
  • negative regulation of transcription
  • induction of apoptosis
  • myeloid cell differentiation
    • PATHWAY
    metabolism
    signaling
    a component
  • colocalizing and interacting with CREBBP, TIF2A and with DAXX in special (PML/SP100) nuclear bodies(NB/POD), to form a retinoic acid (RA) dependent growth suppressive RRXA, RARA nuclear
  • AXIN1, PML and TP53 form a ternary complex
    • INTERACTION
    DNA binding to interferon stimulated response element (ISRE) and GAS motif in the 5'UTR
    RNA
    small molecule metal binding,
  • Zn2+
    • protein
  • HDAC1
  • HAT
  • viral transactivator
  • inhibits NR4A1 (NUR77) mediated transcription
  • SIRT1
  • TOPBP1
  • TRIM27 and TRIM69
  • C-terminus of ELF4
  • Lassa virus Z protein
  • mTOR
  • several transcription factors and their coactivators: HIPK2 and EP300
  • HIPK2
  • Aurora Kinase A (AURKA)
  • p53 ubiquitin-ligase Mdm2
  • Oncoprotein Mdm2
  • nucleolar protein L11
  • Myc
  • bonds and augments the transcriptional activities of Aryl hydrocarbon receptor nuclear translocator (ARNT)
  • cyclin T1 (CCNT1)
  • Checkpoint protein with FHA and ring finger domains (CHFR)
  • CREBBP
  • death-domain associated protein (DAXX)
  • Eukaryotic translation initiation factor 4E (eIF4E)
  • involved in the AP-1 complex and can modulate Fos-mediated transcriptional activity
  • GATA binding protein 2 (GATA2)
  • Histone deacetylase 1 and 2 (HDAC1, HDAC2)
  • proline-rich homeodomain protein PRH
  • inhibitor of SAPK2/p38 mitogen-activated protein kinase
  • retinoic acid receptor-alpha (RARalpha), c-Ski, N-CoR, mSin3A and tumor suppressor Mad
  • c-Myb
  • Interacts and inhibits Nur77-mediated transcription
  • regulate the subcellular distribution of the retinoblastoma protein (pRb) and the protein phosphatase 1 alpha (PP1a), triggering pRb dephosphorylation
  • is a transcriptional repressor of NF-kappaB by interacting with RelA/p65
  • prostate-apoptosis-response-4 (Par-4)
  • Transcription factor Sp1
  • Serum response factor (SRF)
  • STAT3, PIC1
  • thymine DNA glycosylase (TDG)
  • Tif1alpha
  • stabilizes the DNA damage response protein TopBP1
  • acts as a transcriptional co-activator with p53
  • Ret finger protein (rfp)
  • Promyelocytic leukemia zinc finger (PLZF)
  • ring finger protein 36 (RNF36)
  • ankyrin repeat domain 2 (ANKRD2)
  • CREB binding protein (CREBBP)
  • immediate target gene regulated by IRF8 in response to IFNG activation
  • PML and TBX2 act in an autoregulatory loop to control the effective execution of the senescence program 7)
  • circadian clock regulator that can physically interact with PER2
  • PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA
  • regulates endothelial cell migration, in part, by modulating expression of downstream genes, such as ITGB1
  • undergoes ubiquitination-mediated degradation facilitated by an E3 ligase UHRF1
    • cell & other
    REGULATION
    inhibited by IFN-gamma and LPS
    Other regulated by casein kinase 2 at protein levels by promoting its ubiquitin-mediated degradation dependent on direct phosphorylation at Ser517
    ubiquitinated via the action of UBE3A
    upregulated by oncogenic RAS
    acetylated at K487 and its deacetylation by SIRT1 promotes PML control of PER2 nuclear localization
    ASSOCIATED DISORDERS
    corresponding disease(s) PML
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral germinal mutation      
    mutated in acute promyelocytic leukemia with associates with poor prognosis and RA unresponsiveness
    tumoral fusion      
    fused with RARA int (15;17) in acute promyelocytic leukemia
    Susceptibility to Paget disease (PDB)
    Variant & Polymorphism other
  • rs5742915 strongly associated with PDB
    • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancer  
    PML-RARA degradation or therapy-triggered degradation of oncoproteins could be a general strategy to eradicate cancer stem cells
    ANIMAL & CELL MODELS
  • PMLRAR alpha transgenic mice exhibited neutrophil differentiation impairment and acute promyelocytic leukemia
  • Pml–/– mice had smaller brains and hippocampus than Pml+/+ and Pml+/– mice although the overall organization of the brain did not appear to be affected
  • PML-RARA-targeted DNA vaccine induces protective immunity in a mouse model of leukemia