Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway
Abstract
:1. Introduction
2. E3 Ligases for p53
2.1. MDM2/MDMX
2.2. Pirh2
2.3. COP1
2.4. CHIP
2.5. HUWE1
2.6. TRIM Proteins (TRIM24, TRIM28, TRIM29, TRIM39, TRIM69, and TRIM71)
2.7. RING1
2.8. FBW7α
3. E3 Ligases for p63 and p73
3.1. NEDD4
3.2. ITCH
3.3. WWP1
3.4. Pirh2
3.5. MDM2/MDMX
4. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
TAD | Transactivation domain |
MDM2 | Mouse double minute 2 |
Pirh2 | p53 induced with a RING-H2 domain protein |
CHIP | Carboxyl terminus of Hsc70 interacting protein |
HUWE1 | HECT, UBA, and WWE domain-containing E3 ubiquitin ligase 1 |
KO | Knockout |
RING1 | Ring finger protein 1 |
FBW7 | F-box and WD repeat domain-containing protein 7 |
Itch/AIP4 | Itchy E3 ubiquitin protein ligase/atrophin-1 interacting protein 4 |
WWP1 | WW domain-containing E3 ubiquitin protein ligase 1 |
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E3 Ligase | Phenotype of KO Mice | General Role in Cancer | p53 Interaction Site | Year # |
---|---|---|---|---|
MDM2 | Embryonically lethal [44,45] | p53 dependent and independent oncogenesis [46,47,48,49,50,51,52,53,54,55] | 1–51 aa and C-terminus [56,57] | 1997 [8] |
MDMX | Embryonically lethal [58,59,60] | Oncogene [54,55,61,62] | 2000 [63] | |
PIRH2 | Predisposed to tumorigenesis [64] | Oncogene [65,66,67] Tumor Suppressor [64] | 82–292 aa and the tetramerization domain [68] | 2003 [68] |
COP1 | Embryonically lethal [69] | Oncogene [70,71,72,73] Tumor Suppressor [69,74] | Regions within the DNA-binding domain [75] | 2004 [76] |
TOPORS | Viable but high perinatal mortality, genomic instability [77] | Tumor Suppressor [77,78,79,80] Oncogene [81] | 2004 [82] | |
CHIP | Sterile, high levels of protein oxidation and lipid peroxidation, reduced antioxidant defense system and energetic status [83], sensitive to heat stress [84] | Oncogene [85] | DNA binding domain in p53, Hsp70 and CHIP complex [86] | 2005 [87] |
HUWE1 (ARF-BP1, MULE) | Embryonically lethal [88] | Tumor suppressor [89,90,91] Oncogene [92,93,94,95] | 2005 [96] | |
TRIM28 | Embryonically lethal [97] | Oncogene [98] | 2005 [99] | |
CARP1/2 | CARP2 KO showed no abnormality [100] | 2007 [101] | ||
SYNOVIOLIN | Embryonically lethal [102] | 2007 [103] | ||
TRIM 24 | Metastatic HCC [104] | Liver specific Tumor Suppressor [104] Oncogene in breast cancer [105,106,107] | 2009 [108] | |
JFK/SKP1-CUL1-F-box | Oncogene in breast cancer [109] | 2009 [110] | ||
MKRN1 | Senescence and tumorigenesis in gastric cancer [111] | 2009 [112] | ||
TRIM 39 | 2012 [113] | |||
TRIM 71 | Embryonically lethal [114,115] | Tumor suppressor by degrading mutant p53 [116] | TA domain of mutant p53 [116] | 2017 [117] |
RING1 | Oncogene [118] | 2018 [118] | ||
FBW7α | Tumorigenic [119] | Oncogene [120] Tumor Suppressor [119,121,122,123,124,125,126,127,128] | 2019 [120] | |
TRIM 69 | Increased metabolic disorder after high fat diet treatment [129] | 2019 [130] |
Name | Type | Phenotype of KO Mice | General Role in Cancer | Year * |
---|---|---|---|---|
E6 HPV oncoprotein-E6AP complex | Only in HPV infected cells | Viable but small prostate gland, increased p53 protein levels in prostrate [131] | 1990 [132] | |
P300/MDM2 | E4 ligase | Embryonic lethal [133] | Oncogene and tumor suppressor [134] | 1998 [135] |
E4ORF6 and E1B55K | 2001 [136] | |||
ICP0 | HSV1 Viral Oncoprotein targeting p53 for translocation | 2003 [137] | ||
UBC13 | E2 conjugating enzyme causing proteasome independent degradation- cytosolic localization, tetramerization inhibition | Embryonic lethal [138] | Oncogene [139,140] | 2006 [141] |
E4F1 | An atypical E3 ligase (lacking HECT/RING), does not cause degradation or nuclear transport but carry out localization to chromatin | Embryonic lethal [142] | Oncogene [143,144] | 2006 [145] |
TRIM 29 | TRIM protein lacking RING finger | Increased macrophage production [146] | Oncogene [147,148,149] Tumor Suppressor [150,151] | 2010 [152] |
UBE4b | E4 Ligase | Embryonic lethal [153] | Oncogene in breast cancer [154] Tumor suppressor [155,156] | 2011 [157,158] |
E3 Ligase | Isoform Specificity | Phenotype of KO Mice | General Role in Cancer | p63 Interaction Site | Year # |
---|---|---|---|---|---|
MDM2 | TAp63α * TAp63γ * | Embryonically lethal [44,45] | Oncogene [46,47,48,49,50,51,52,53,54,55] | TA Domain [200] | 2001 [175] * |
MDMX | TAp63α * TAp63γ * | Embryonically lethal [58,59,60] | Oncogene [54,55,61,62] | 2001 [175] * | |
NEDD4 | ΔNp63α | Embryonic lethality at mid gestation with heart defects [201] | Both [202] | PPPY motif in SAM domain [203] | 2005 [203] |
ITCH | ΔNp63α ΔNp63α | High rate of proliferation and improved wound healing [204] | Oncogene [205] | 109-120 aa of TAp63 and 15-26 aa of ΔNp63 [206,207] | 2006 [206,207] |
WWP1 | TAp63α ΔNp63α * | Increased rate of bone formation rates [208] | Oncogene in osteosarcoma [209], breast cancer [210,211], and prostate cancer [212] | PPPY motif in SAM domain [213] | 2008 [213] 2010 [214] |
FBW7-MDM2 | ΔNp63α | Embryo lethality at day 10.5 due to defects in cardiovascular development [215,216] | Oncogene [120] Tumor Suppressor [119,121,122,123,124,125,126,127,128] | Region surrounding S383 [217] | 2010 [217] |
PIRH2 | TAp63α ΔNp63α | Oncogene [67,71,72] Tumor Suppressor [64] | 2013 [218] |
E3 Ligase | Isoform Specificity | Phenotype of KO Mice | General Role in Cancer | p73 Interaction Site | Year # |
---|---|---|---|---|---|
MDM2 | TAp73α * TAp73β * ΔNp73α ** | Embryonically lethal [44,45] | Oncogene [46,47,48,49,50,51,52,53,54,55] | TA Domain [200] SAM Domain [222] | 1999 [170,171,172] * |
MDMX | TAp73α * TAp73β * | Embryonically lethal [58,59,60] | Oncogene [54,55,61,62] | 2001 [174] * | |
ITCH | TAp73α ΔNp73α | High rate of proliferation and improved wound healing [204] | Oncogene [205] | PY region just before the SAM domain of p73, and particularly the Y487 aa residue of TAp73 [219] | 2005 [219] |
FBXO45 | TAp73α | SAM domain [223] | 2009 [223] | ||
PIR2/RNF144B | ΔNp73α | Oncogene [224] | 2010 [225] | ||
PIRH 2 | TAp73α * TAp73β | Predisposed to tumorigenesis [64] | Oncogene [66,67,71] Tumor Suppressor [64] | 2011 [166,167] * | |
TRIM 32 | TAp73α | Myopathy and neurological deficiencies [226] AD- atopic dermatitis-like inflammatory skin condition [227] | Oncogene [228] | 2013 [229] | |
WWP2-WWP1 Complex | ΔNp73α | 2014 [230] | |||
HADES | 2015 [231] |
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Bang, S.; Kaur, S.; Kurokawa, M. Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway. Int. J. Mol. Sci. 2020, 21, 261. https://doi.org/10.3390/ijms21010261
Bang S, Kaur S, Kurokawa M. Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway. International Journal of Molecular Sciences. 2020; 21(1):261. https://doi.org/10.3390/ijms21010261
Chicago/Turabian StyleBang, Scott, Sandeep Kaur, and Manabu Kurokawa. 2020. "Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway" International Journal of Molecular Sciences 21, no. 1: 261. https://doi.org/10.3390/ijms21010261