PML
a zinc-finger protein that regulates a wide range of cellular processes including transcriptional regulation, senescence, DNA damage response, glycolysis, tumor suppression, apoptosis, and viral defense activity against DNA and RNA viruses. Its antiviral activity can involve one or several isoform(s) and can be enhanced by the permanent PML-NB-associated protein DAXX or by the recruitment of p53 within these structures. PML also regulates transcription activity of ELF4 and can act as an important mediator for TNF-alpha- and IFN-alpha-mediated inhibition of endothelial cell network formation and migration. Various isoforms localize in different subcellular locations. Many are reported to have distinct functions. Nuclear PMLs can localize to PML-nuclear bodies (PML-NBs), where they function as scaffolds, allowing other proteins to shuttle in and out, a process regulated by SUMO-mediated modifications and interactions. Sumoylated forms interact with SATB1 and localize to the PML-NBs. Sumoylation on three sites is required for nuclear body formation. Sumoylation on Lys-160 is a prerequisite for sumoylation on Lys-65. The B1 box and the RING finger are also required for localization to nuclear bodies. Nuclear isoforms (isoforms-1, -8, -9, -5, -2), in concert with SATB1, are involved in local chromatin-loop remodeling and gene expression regulation, for example, at the MHC-I locus. Interacts with SIRT1, TOPBP1, TRIM27 and TRIM69. Isoform-8 is required for efficient IFN-gamma induced MHC II gene transcription via regulation of CIITA. Isoform-9 exhibits antiviral activity against poliovirus by inducing apoptosis in infected cells. Represses human foamy virus (HFV) transcription. Isoform-5 has a multifaceted role in the regulation of apoptosis and growth suppression: activates RB1 and inhibits AKT1 via interactions with PP1 and PP2A phosphatases respectively, negatively affects the PI3K pathway by inhibiting MTOR and activating PTEN, and positively regulates p53 by acting at different levels (by promoting its acetylation and phosphorylation and by inhibiting its MDM2-dependent degradation). Acts as a transcriptional repressor of TBX2 during cellular senescence and the repression is dependent on a functional RBL2-E2F4 repressor complex. Regulates double-strand break repair via its interaction with WRN. Acts as a negative regulator of telomerase by interacting with TERT. Regulates PER2 nuclear localization and circadian function. Isoform-5 restricts varicella zoster virus (VZV) via sequestration of virion capsids in PML-NBs. Sumoylated isoform-5 restricts rabies virus by inhibiting viral mRNA and protein synthesis. Isoform-8 may enhance adenovirus transcription. Cytoplasmic forms regulate glycolysis by inhibiting the enzymatically active tetrameric form of PKM2, and are involved in the regulation of the TGF-beta signaling pathway. Twelve alternatively-spliced human isoforms have been reported. Isoform-4 inhibits specifically the activity of the tetrameric form of PKM. Shows restriction activity towards human cytomegalovirus (HCMV) and influenza A virus strains PR8(H1N1) and ST364(H3N2). The cytoplasmic isoform-14 can restrict herpes simplex virus-1 (HHV-1) replication by sequestering the viral E3 ubiquitin-protein ligase ICP0 in the cytoplasm. A chromosomal aberration involving PML can cause acute promyelocytic leukemia (APL). 12 alternatively-spliced human isoforms have been reported. Note: This description may include information from UniProtKB.
Protein type: Nucleolus; Oncoprotein; Transcription factor; Tumor suppressor; Ubiquitin conjugating system
Molecular Function: cobalt ion binding; DNA binding; metal ion binding; protein binding; protein heterodimerization activity; protein homodimerization activity; SMAD binding; SUMO binding; transcription coactivator activity; ubiquitin protein ligase binding; zinc ion binding
Biological Process: activation of cysteine-type endopeptidase activity involved in apoptotic process; apoptotic process; branching involved in mammary gland duct morphogenesis; cell aging; cell cycle arrest; cell fate commitment; cellular response to interleukin-4; cellular response to leukemia inhibitory factor; cellular senescence; circadian regulation of gene expression; common-partner SMAD protein phosphorylation; defense response to virus; DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; endoplasmic reticulum calcium ion homeostasis; entrainment of circadian clock by photoperiod; extrinsic apoptotic signaling pathway; fibroblast migration; immune system process; innate immune response; intrinsic apoptotic signaling pathway by p53 class mediator; intrinsic apoptotic signaling pathway in response to DNA damage; intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator; intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress; intrinsic apoptotic signaling pathway in response to oxidative stress; maintenance of protein location in nucleus; myeloid cell differentiation; negative regulation of angiogenesis; negative regulation of cell growth; negative regulation of cell proliferation; negative regulation of interleukin-1 beta secretion; negative regulation of interleukin-1 secretion; negative regulation of mitotic cell cycle; negative regulation of telomerase activity; negative regulation of telomere maintenance via telomerase; negative regulation of transcription, DNA-templated; negative regulation of translation in response to oxidative stress; negative regulation of ubiquitin-dependent protein catabolic process; negative regulation of viral release from host cell; PML body organization; positive regulation of apoptotic process involved in mammary gland involution; positive regulation of apoptotic signaling pathway; positive regulation of defense response to virus by host; positive regulation of extrinsic apoptotic signaling pathway; positive regulation of fibroblast proliferation; positive regulation of histone deacetylation; positive regulation of MHC class I biosynthetic process; positive regulation of protein localization to chromosome, telomeric region; positive regulation of telomere maintenance; positive regulation of transcription by RNA polymerase II; proteasome-mediated ubiquitin-dependent protein catabolic process; protein import into nucleus; protein stabilization; protein targeting; protein-containing complex assembly; regulation of calcium ion transport into cytosol; regulation of cell adhesion; regulation of circadian rhythm; regulation of double-strand break repair; regulation of MHC class I biosynthetic process; regulation of protein phosphorylation; regulation of transcription, DNA-templated; response to cytokine; response to gamma radiation; response to hypoxia; response to UV; retinoic acid receptor signaling pathway; rhythmic process; transforming growth factor beta receptor signaling pathway; viral process
