Table 2.
A summary of the 14-3-3 PPIs that are directly implicated or have a putative role in the regulation of p53, and the desired strategy for developing novel antineoplastic therapies.
| 14-3-3-binding partner | 14-3-3 isoform | Binding mode | p53 regulation | Therapeutic strategy | Review (key refs.) |
|---|---|---|---|---|---|
| Direct link between 14-3-3 PPI and p53 regulation | |||||
| p53 | γ | Phosphorylation dependent (pS366, pS378, pT387; monovalent) | •Increases p53 transcriptional activity | Stabilisation (e.g. FC-A) | 2.1 (12–19) |
| ε |
•Enhances p53 binding to DNA •Increases p53 transcriptional activity |
||||
| ζ | |||||
| σ | Phosphorylation dependent (pS366, pS378, pT387; monovalent) Non-canonical interaction: 14-3-3 CTD (amino acids: 153–248) |
•Increases p53 protein levels •Increases p53 transcriptional activity |
2.2 (20–27) | ||
| τ | |||||
| MDM2 | σ |
Phosphorylation dependent (unknown sites) Non-canonical interaction(s): MDM2 CTD (amino acids: 440–491) 14-3-3 CTD (amino acids: 153–248) |
•Increases p53 protein levels •Increases p53 transcriptional activity |
Stabilisation | 3.1.1-2 (35–37) |
| (α)β, γ, ε, η, ζ, τ | Phosphorylation dependent (pS166 and pS186; bivalent) | •Not known | ? | 3.1.3–4 (40) | |
| MDMX | (α)β, γ, ε, η, ζ, τ | Phosphorylation dependent (pS342 and pS367; bivalent) | •Increases p53 protein levels | Stabilisation | 3.2 (55, 57-62) |
| COP1 | σ | Phosphorylation dependent (pS387; monovalent) |
•Increases p53 protein levels •Increases p53 transcriptional activity •Inhibits p53 nuclear export |
Stabilisation | 3.3 (63–65) |
| SIRT2 | (α)β, γ | Phosphorylation dependent (putative site: pS368; monovalent) | •Decreases p53 transcriptional activity | Inhibition | 4.1 (82) |
| No direct link between 14-3-3 PPI and p53 regulation | |||||
| HDAC4 | (α)β, ε | Phosphorylation dependent (pS246, pS467, pS632; bivalent) |
•HDAC4 cytoplasmic sequestration •Putative: Increases transcription of p53 pro-survival target genes |
Inhibition | 4.2 (87–89) |
| HDAC5 | (α)β, ε | Phosphorylation dependent (pS259, pS498, pS661; bivalent?) |
•HDAC5 nuclear exclusion and cytoplasmic sequestration •Putative: Inhibits p53 acetylation (K120) and increases transcription of pro-apoptotic genes |
Stabilisation | 4.3 (87–89) |
| HDAC7 | ε | Phosphorylation dependent (pS155, pS358, pS486; monovalent) |
•Increases HDAC7 levels but promotes cytoplasmic accumulation. •Implications for p53 regulation are unclear |
? | 4.4 (91, 95–96) |
| Chk1 | (α)β, ζ, σ | Phosphorylation dependent (pS345; monovalent?) |
•Chk1 nuclear accumulation •Putative: promotes p53 phosphorylation and stabilisation |
Stabilisation | 5.1 (111–114) |
| BTK | ζ | Phosphorylation dependent (pS51, pT495; bivalent) |
•BTK nuclear exclusion and ubiquitination •Putative: prevents BTK-mediated p53 phosphorylation and stabilisation |
Inhibition | 5.2 (123) |
| ASK1 | ζ | Phosphorylation dependent (pS966; monovalent) |
•ASK1 inhibition. •Putative: prevents p53 activation via the p38/JNK pathways |
Inhibition | 5.3 (128–129) |
| AKT | σ | Non-canonical interaction: 14-3-3 CTD (amino acids: 1–147) |
•AKT inhibition •Putative: stabilises p53 by preventing MDM2 phosphorylation. |
Stabilisation | 5.4 (37) |