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Table 3 Overview of PML physiological function and the corresponding phenotypes in Pml−/− mouse

From: PML: Regulation and multifaceted function beyond tumor suppression

Physiological function Pml−/− mouse phenotype Known key cellular mechanism
Tumor suppression 1. Susceptible to carcinogen/oncogene-induced tumorigenesis [4, 5] 2. Resistant to irradiation-induced death [5] 1. TGFβ→cPML→Smad2/3 and SARA→apoptosis [8] 2. RAS→P53→PML→Cell senescence and apoptosis [33, 105] 3. DDR→PML-|MDM2-|P53→apoptosis [67] 4. PML-|Daxx→HAUSP-|PTEN→apoptosis [102] 5. PML-|RB-E2F→Cell survival [78] 7. PML→PP2A-|Akt→Cell survival [4, 10] 8. IFN→PML→TRAIL→apoptosis [141] 9. TNF→PML-|NF-κB→A20/survivin expression-| apoptosis [143, 144] 10. FAS/Osmotic stress→PML→DAXX-|anti-apoptotic gene expression [97]
Hematopoietic stem cell renewal 1. Loss of CML-like phenotype in p210BCR-ABL /Pml−/− mouse model [114] 2. Exhaustion and reduced quiescence in Pml−/− hematopoietic stem cells [114] 1. PML→PPARδ→fatty acid oxidation→HSC asymmetric division [114]
Neuron function, development and brain cognitive ability 1. Small brain size [94] 2. Defects in cortex development and macroglia differentiation [94] 3. Loss of learning and memory consolidation [147] 4. Lower anxiety-associated response [146] 5. Loss of Pml aggravates the neurodegenerative phenotype in SCA1 mouse model [100] 6. Loss of precision and stability in circadian rhythm [76] 1. PML→PP1α→Rb→neural progenitor cell fate regulation [94] 2. Neural activity stimuli→Arc→PML-NB-| GluA1→homeostatic plasticity [147] 3. PML E3 SUMO ligase activity→PolyQ-ATXN7/ATXN1-sumoylation→RNF4-mediated ubiquitination and degradation [100] 4. Sirt1→PML→PER2→BMAL1/CLOCK→circadian rhythm [76] 5. As2O3-|PML→c-Myc→glioblastoma stem cell growth [113]
Mammary gland development and triple-negative breast cancer stem cell maintenance 1. Impaired development of mammary ductal and alveolar structure [34] 2. Defects in mammary progenitor cell fate determination [34] 1. Stat3/Stat5/Stat6-mediated Pml regulation is required for normal mammary gland development [34] 2. PML→Sirt1→Ac-GPC1α→GPC1α →PPARδ→Fatty acid oxidation gene expression→breast cancer stem cell survival [115]
Metabolism 1. Slim body, higher body temperature and high energy usage rate in a high fat diet [118] 2. Elevated AMPK Activation in liver and muscle in normal chow or Western diet [118] 3. Reduced lipid metabolic gene expression in Pml−/− mouse liver; in this study, Pml−/− mouse is prone to obese conditiona [115] 4. Loss of Pml promotes adipogenesis and adipogenic transcription factor activitya [121] 1. PML-|AMPK→FAO→metabolism [118] 2. PML→PPARδ→FAO→HSC self-renewal [114] 3. PML→Sirt1→Ac-GPC1α→GPC1α →PPARδ→FAO gene expression→breast cancer stem cell survival [115] 4. p53→PML (MAM localization)-|AMPK-mTOR-ULK1→mitochondria calcium transfer→autophagy [9]
Anti-viral infection 1. Susceptible to liver tumor in HCV transgenic mouse [132] 2. Pml−/− MEFs are susceptible to viral infection [129] 1. (ICP0, BZLF1 and IE1)-|PML (PML NB disassembly)→anti-HSV1 [123,124,125,126] 2. PML -| 3D polymerase→virus propagation [127] 3. PML cytosolic translocation -|HIV viral genome [128]
Innate immunity and inflammatory response 1. Severe granulomatous lesion and botryomycosis in Pml−/− mice upon bacterial infection [134] 2. Impaired macrophage function [134, 135, 158] 3. Low acute inflammatory response [134, 135] 1. IFN→PML→STAT1→anti-viral gene and inflammatory gene expression [127, 136, 137] 2. IFNγ→PML→CTIIA→MHC-II expression [138] 3. PML-| Pin1-|IRF3→IFNβ expression [139] 4. PML→NLRP3 inflammasome assembly→IFNβ maturation [135] 5. HCMV→IE1-|PML→STAT1/STAT2→ISGs expression [140] 6. IFN→PML→TRAIL→apoptosis [141] 7. TNF→PML-|NF-κB→A20/survivin expression-| apoptosis [143, 144] 8. FAS→PML-|Daxx-|anti-apoptotic gene expression [11, 97, 106]
Angiogenesis 1. Increased neovascularization upon ischemia [152] 2. Compromised IFNα-mediated angiostatic activity ex vivo in Pml knockout mouse [110] 1. Hypoxia: PML-|mTOR-Rheb→HIF1→angiogenesis [152] 3. Carcinoma-| SCP1/SCP3→PML-|angiogenesis [153] 4. Tumor microvesicle→miR1246-|PML-| angiogenesis [35] 5. TNF→P38→MNK1→PML-| angiogenesis [37]
  1. PML is a versatile protein involved in several physiological functions. Here, we listed most of them, including tumor suppression, stem cell maintenance, neural and mammary development, metabolism, anti-virus, immunity and angiogenesis. We summarized the phenomenal phenotypes shown in Pml−/− mouse. Also, we listed key reported mechanisms regarding with each physiological function
  2. cPML cytoplasmic PML
  3. aPml/− mice show obese phenotype)