Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging
Abstract
1. Introduction
2. The Canonical p53 Pathway
3. p53 Isoforms
4. The ∆40p53 Isoform
4.1. Mechanism of Production
4.2. The In Vitro Function of ∆40p53
4.2.1. Modulation of Transcription of p53-Target Genes
4.2.2. Cell-Cycle Regulation
4.2.3. Apoptosis
4.2.4. Senescence
4.3. Why Is ∆40p53 Functionally Distinct to p53?
4.4. ∆40p53 in Cancer Prognostication and Clinical Outcomes
4.5. The Role of ∆40p53 in Aging
5. Can ∆40p53 Be Targeted to Modulate the p53 Pathway?
5.1. Modulation of ∆40p53 Using Compounds Already Used Clinically (In Vivo)
5.1.1. HDM2 Antagonists
5.1.2. Endoplasmic Reticulum (ER) Stress
5.1.3. 20S Proteasome Targeting
5.2. Modulation of ∆40p53 Using In Vitro Strategies
5.2.1. Transfection and Transduction for Exogenous Expression
5.2.2. Antisense Oligonucleotides
5.2.3. RNA Interference and CRISPR/Cas9
5.2.4. Targeting the G-Quadruplex (G4) Structure
6. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Type of Cancer | Cell Line | Role/Mechanism of Action | Approach Used to Modulate Δ40p53 Expression | Reference |
---|---|---|---|---|
Hepatocellular carcinoma | HuH-1 (TP53WT), HepG2 (TP53WT), HEP3B (TP53−/−, HuH-7 (TP53Y220C), PLC/PRF/5 (TP53R249S) human hepatocellular carcinoma cell lines | Tumour suppressor role Promotion of cellular senescence (increase in percentage of SA-β-gal-positive cells) Suppression of clonogenicity Inhibition of cell proliferation Cell cycle arrest at G1 phase Increase in p21WAF1, HDM2, FAS, IL-8 and GADD45A expression Increase in protein half-life of FLp53 | Vector targeted deletion of TP53 exon 2 Retroviral plasmid transduction with constructs containing ORF of Δ40p53 Knockdown of p53 by using retroviral plasmids and CRISPR/Cas9 Inhibition of HDM2 (MG132 inhibitor) | [64] |
Melanoma | Mel-FH, Mel-MC, Mel-CV, Mel-RM, MM200, Me1007, Me4405, IgR3, MM186, Mel-KN, Mel-JD, MM283, Mel 4.1, Mel-FC, MM415, MM486, MV3, Sk-Mel-110 and Sk-Mel-28 melanoma cell lines | Expressed at low levels in normal cells but highly expressed in tumour cells Overexpression inhibited transcriptional activation of PUMA and p21WAF1 at the basal level and following treatment with DNA damaging agents | Transduction of construct pCIN4.p47 containing the ORF of Δ40p53 | [5] |
A375 melanoma cell line | Increase in number of dead cells Reduction of skin cancer cell viability Induction of apoptosis Increase in p53, p21WAF1 and PIDD gene expression Creation of nuclear tetramers with endogenous, serine 15–phosphorylated p53 | Transduction with a construct containing the ORF of Δ40p53 | [66] | |
Osteosarcoma | Saos-2 osteosarcoma cell line | Formation of oligomers with p53 Inhibits transcriptional activation of target genes when expressed in excess of FLp53 | Transfection using pcDNA3-TAp53 (mut40—ATG40 > TTG) and pcDNA3-Δ40p53 vectors | [20] |
Lung cancer | H1299 lung cancer cell line (p53 null) | Formation of oligomers with p53 Suppression of FL-p53 transcriptional activity in an incremental manner Reduction of p21WAF1 protein expression when Δ40p53 is overexpressed Enhancement of the pro-apoptotic activity of p53 | Transfection using pcDNA3-TAp53 (mut40—ATG40 > TTG) and pcDNA3-Δ40p53 vectors | [20] |
Colon cancer | HCT116-p53(–/–) (endogenous Δ40p53 expression), HCT116-p53(+/+) (wild-type p53) colon carcinoma cell lines | Enhancement of the pro-apoptotic activity of p53 | Transfection with adenoviral delivery of a Δ40p53 plasmid | [67] |
Endometrial cancer | Ishikawa, RL-95–2, AN3CA and KLE endometrial cancer cell lines | Major component of p53 amyloid aggregates | None | [68] |
Breast cancer | p53 MT cell lines (T47D, MDA-MB-231, HMT-3522-T42) and wtp53 cell lines (ZR-75-1 and MCF7) | Upregulated in tumour cell lines when compared to normal breast epithelial cell lines | None | [69] |
Mechanism | Effect on ∆40p53 | Effect on FLp53 * | Reference | |
---|---|---|---|---|
Targeting alternative splicing (retention of intron 2) | siRNA targeting transcripts that retain intron 2 | ↓ | ? | Hypothetical |
Site directed mutagenesis of G in intron 3 | ↑ | ↓ (mRNA) | [52] | |
stabilisation of G4 through 360A, PhenDC, K+ | ↓ | ↑ (mRNA) | [52] | |
Damage to non-G4 transcripts through ionizing radiation | ↓ | ? | [52] | |
Destabilisation of G4 through Na+ | ↑ | ? | [52] | |
CRISPR interference inhibiting translation of p53 transcripts retaining intron 2 | ↓ | ? | Hypothetical | |
CRISPR/Cas9 knockout of intron 2 | ↓ | ? | Hypothetical | |
Targeting translation via IRES (exon 4) | Transfection with constructs containing a CTG substitution at 2nd ATG | ↓ | ↑ (protein) | [17] |
Transduction with constructs containing ORF of ∆40p53 | ↑ | ? [5]; none (protein) in p53-null cells [50]; ↑ (protein) [62,64]; | [5,51,64,66] | |
Transfection with constructs containing a hairpin structure near/over first ATG | ↑ | ↓ (protein) | [61] | |
Transfection with construct containing stop codon upstream of IRES | ↑ | ↓ (protein) | [61] | |
Antisense oligonucleotides targeting 5’ end of the p53 transcript | ↑/↓ | ↑/↓ (protein) | [115] | |
Tunicamycin or thapsigargin-induced ER stress | ↑ | ↑ (protein) | [61] | |
CRISPR/Cas9 homology-directed repair of the 1st or 2nd ATG | ↑/↓ | ? | Hypothetical | |
Transfection with constructs containing CTG Substitution at 1st ATG | ↑ | ↓ (protein) | [17] | |
Transduction leading to deletion of the second ATG | ↑ | None (protein) | [21] | |
CRISPR/Cas9 excision of exon 4 | ↓ | ↓ (protein) | [64] | |
Other | Nutlin-3 and MG132 inhibition of HDM2 ubiquitination of FLp53 | ↑;↑FLp53:∆40p53 | ↑ (protein) | [17,64,116] |
Transduction leading to deletion of exon 2 | ↑ | ? | [64] | |
20S proteasome enhancement through manipulated chlorpromazine | ↑ | ? | Hypothetical |
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Steffens Reinhardt, L.; Zhang, X.; Wawruszak, A.; Groen, K.; De Iuliis, G.N.; Avery-Kiejda, K.A. Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging. Cancers 2020, 12, 1659. https://doi.org/10.3390/cancers12061659
Steffens Reinhardt L, Zhang X, Wawruszak A, Groen K, De Iuliis GN, Avery-Kiejda KA. Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging. Cancers. 2020; 12(6):1659. https://doi.org/10.3390/cancers12061659
Chicago/Turabian StyleSteffens Reinhardt, Luiza, Xiajie Zhang, Anna Wawruszak, Kira Groen, Geoffry N. De Iuliis, and Kelly A. Avery-Kiejda. 2020. "Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging" Cancers 12, no. 6: 1659. https://doi.org/10.3390/cancers12061659
APA StyleSteffens Reinhardt, L., Zhang, X., Wawruszak, A., Groen, K., De Iuliis, G. N., & Avery-Kiejda, K. A. (2020). Good Cop, Bad Cop: Defining the Roles of Δ40p53 in Cancer and Aging. Cancers, 12(6), 1659. https://doi.org/10.3390/cancers12061659