Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors
Abstract
:Simple Summary
Abstract
1. Introduction
2. Ubiquitination-Dependent p73 Inhibition
2.1. Itch
2.2. MDM2/MDMX
2.3. Pirh2
2.4. TRIM32
2.5. FBXO45
2.6. UFD2a
2.7. Hades
2.8. The Cul4A–DDB1 E3 Ubiquitin Ligase Complex
2.9. WWP2
3. Phosphorylation-Dependent p73 Inhibition
3.1. Cyclin-Dependent Kinase Complexes
3.2. Protein Kinase A
3.3. Polo-Like Kinase Family Members
3.4. Aurora Kinase-A
3.5. CK2
4. Deacetylation-Dependent p73 Inhibition
5. SUMOylation-Dependent p73 Inhibition
6. Targeting Post-Translational Modifications of p73 for Cancer Therapy
6.1. Targeting the p73 Ubiquitination Pathway
6.2. Targeting of the p73 Phosphorylation Pathway
6.3. Targeting of the p73 Acetylation Pathway
7. Conclusions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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E3 Ligase | TAp73 Isoform | p73 Interaction Site | Effects on p73 | Refs |
---|---|---|---|---|
ITCH | p73α | PY motif (Met 452–Ala 489) | Proteasome-dependent p73 degradation | [43] |
MDM2 | p73α | - | p73α activity inhibition but without promoting its degradation | [55,56] |
p73β | Two residues (F15 and W19) | p73β activity inhibition but without promoting its degradation | [57] | |
p73α | - | p73 degradation through a mechanism involving the interaction of MDM2 with Itch | [45] | |
p73α and p73β | N-terminal domain | p73 ubiquitination but without promoting its degradation | [44] | |
p73α | The C-terminal SAM domain (especially the peptide comprising α4 and α5 helices of SAM) | - | [58] | |
MDMX | p73α | TA domain | Subcellular localization of p73 and inactivation of transcription | [46,59] |
Pirh2 | p73α and p73β | DNA-binding domain | p73 ubiquitination and repressing p73-dependent transcriptional activity | [47] |
TRIM32 | p73α | - | p73 ubiquitination and degradation, inhibiting p73 transcriptional activity | [50] |
FBXO45 | p73α | SAM domain | Proteasome-dependent degradation of p73 | [51] |
UFD2a | p73α | SAM domain | Ubiquitination-independent p73 degradation | [60] |
Hades | - | - | Ubiquitination of p73, promoting its degradation | [61] |
Cul4A–DDB1 complex | p73α | The N-terminal region of p73, encompassing residues 1–320 and including the DNA-binding domain. | p73 monoubiquitination and inhibition of its transcriptional activity without affecting p73 stability | [52] |
WWP2 | p73α and p73β | Oligomerization domain | p73 ubiquitination and its proteasomal degradation in | [53] |
Kinase | TAp73 Isoform | p73 Interaction Site | p73 Phosphorylation Site | Biological Responses | Refs |
---|---|---|---|---|---|
Cyclin A/CDK2, cyclin B/CDK2 | p73α, p73β, p73γ | Two potential CRM sites (position 149, KKL; position 515, RAL) | Thr86 | A decrease in the p73 transcriptional activity on the expression of the p21WAF1 gene | [96] |
PKA-Cβ | p73α | The C-terminal (469–636) and the N-terminal (63–130) regions | N-terminal region (residues 1–130) | A decrease in p73α transcriptional activity on p21WAF1 and Bax genes | [97] |
Plk1 | p73α | NH2-terminal region | Thr27 | A decrease in p73α transcriptional activity on p21WAF1, Bax and MDM genes and its pro-apoptotic activity | [98] |
Plk3 | p73α | NH2-terminal region (the amino acids 63-113) | AA residue(s) (63–113) | A decrease in p73α transcriptional activity on p21WAF1 and the pro-apoptotic Bax and p53AIP1 genes | [99] |
Plk2 | - | TA domain | Ser48 | A decrease in p73 transcriptional activity | [100] |
Aurora Kinase-A | - | DNA-binding domain | Ser235 | A decrease in the ability of p73 for DNA-binding and its transactivation activity and inhibition of apoptosis | [101] |
CK2 | - | N-terminal domain | T27 | A decrease in p73 transcriptional activity and an increase in the expression of several markers of cancer stem cells including Nanog, Oct4 and Sox2 | [102] |
Drug | FDA-Approved Drug | Target Pathway | Suggested Mechanism(s) of Action | Biological Responses | Refs |
---|---|---|---|---|---|
Protoporphyrin IX | Metvix® | Ubiquitination | Disruption p73/MDM2 and p73/MDMX complexes and inhibition of p73/Itch interaction [67]. | Activation and stabilization of p73 and induction of p73-dependent apoptosis [134]. Upregulation of NOXA and PUMA expression [67]. | [67,134,135] |
Panobinostat | Farydac® | Ubiquitination | Decrease in the levels of Itch through E2F1 and myc-regulated transcription induction in the levels of miR106b | Increase in the expression of p73 protein and its downstream pro-apoptotic target PUMA with subsequent induction of apoptosis, without affecting the levels of p53. | [42] |
Thymoquinone | Ubiquitination [62] Acetylation [136] | Increase in the expression of p73 protein and induction of apoptosis. | [62,136] | ||
Cisplatin | Platinol® | Phosphorylation |
| Increase in the expression of p73 protein and the induction of apoptosis. | [137,138,139,140] |
Doxorubicin | Doxil® | Phosphorylation [139] Acetylation [119] | Increase in the expression of p73 protein [139] and activation of its pro-apoptotic activity [116,119]. | [116,119,139,141] | |
Camptothecin | - | Phosphorylation | The activation of JNK [139]. | Increase in the expression of p73 protein. | [139] |
Arsenic trioxide | Trisenox® | Acetylation and phosphorylation [142] | Increase in p300–p73 interaction and p73α tyrosine phosphorylation. | Increase in the expression of p73α protein and a decrease in ΔNp73 activation of p73α pro-apoptotic activity. | [142] |
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Omran, Z.; H. Dalhat, M.; Abdullah, O.; Kaleem, M.; Hosawi, S.; A Al-Abbasi, F.; Wu, W.; Choudhry, H.; Alhosin, M. Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors. Cancers 2021, 13, 1916. https://doi.org/10.3390/cancers13081916
Omran Z, H. Dalhat M, Abdullah O, Kaleem M, Hosawi S, A Al-Abbasi F, Wu W, Choudhry H, Alhosin M. Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors. Cancers. 2021; 13(8):1916. https://doi.org/10.3390/cancers13081916
Chicago/Turabian StyleOmran, Ziad, Mahmood H. Dalhat, Omeima Abdullah, Mohammed Kaleem, Salman Hosawi, Fahd A Al-Abbasi, Wei Wu, Hani Choudhry, and Mahmoud Alhosin. 2021. "Targeting Post-Translational Modifications of the p73 Protein: A Promising Therapeutic Strategy for Tumors" Cancers 13, no. 8: 1916. https://doi.org/10.3390/cancers13081916