Table 1.
Regulators that alter mutant TP53 stability and activity.
| Upstream Regulators | Mutant TP53 | Modified Amino Acids |
Samples/Cell Lines | Outcomes/Effects | References |
|---|---|---|---|---|---|
| Phosphorylation | |||||
| Ras signaling | R280K | S6, S9 | MDA-MB-231 | Mutp53/Smad2/TP63 Complex inhibit TP63’s metastasis suppressor function. | [73] |
| DNA damage | R248W, R273H | S15 | MEFs, PANC1 | Constitutively activated DNA damage could account for mutp53 stabilization or nuclear accumulation via S15 phosphorylation. | [41,47,74] |
| NF-κB inhibition by IκB overexpression | P223L/V274V | S15 | DU145 | NF-κB inhibition in DU145 cells leads to S15 phosphorylation of mutp53 via GADD45α-mediated JNK1 activation and potential restoration of wtp53. | [75] |
| Stathmin1 | R175H, R273H | S15, S37 | TOV112D, MDAH-2774 | Stathmin1 enhances interaction of mutp53 with DNA-PK, phosphorylation of mutp53 at S15 and S37 by DNA-PK, and mutp53 stabilization, leading to increased viable cell proliferation. | [76] |
| PML | R175H, R273H, R273H/P309S | Not specified (maybe via phosphorylation at T18 and S46 in mutp53 likewise wtp53) | SKBR3, HT29, SW48 | PML interacts with mutp53 and is required for proliferation and colony formation of cancer cells bearing mutp53; however, it is unclear whether PML promotes phosphorylation of mutp53 like wtp53. | [77] |
| Pin1 | Mouse R172H, R280K | Not specified (maybe via isomerization of phosphorylated S46-P47 site in mutp53 likewise wtp53) | MEFs, MDA-MB-231 | Homozygous deletion of Pin1 attenuates tumor progression in TP53R172H/R172H mice, while Pin1 enhances migration and lung colonization of MDA-MB-231 cells in a manner dependent on mutp53 by enhancing inhibitory interaction of mutp53 with TP63; however, it is unclear whether observed phenotypes by Pin1 are mediated through its detection of phosphorylated S46-P47 site in mutp53. | [78] |
| PLK2 | R175H, R273H | T377 | H1299, SKBR3 | PLK2 phosphorylates mutp53 at T377 and enhances binding of mutp53 with p300, acetylation of mutp53, and mutp53 GOF activity, including increased cell proliferation, NF-Y’s transcriptional activity, and Adriamycin resistance. | [79] |
| Not specified/oncogenic signaling | Not Specified | S392 | Cancer tissues (esophageal squamous cell carcinoma, urothelial transitional cell carcinoma) | S392 phosphorylation in mutp53 is correlated with high levels of Ki67 staining, lymphatic invasion, and poor prognosis, as well as enhanced hetero-oligomerization with wtp53 and dominant-negative activities. | [70,80,81] |
| Acetylation | |||||
| TRRAP | R248Q, R248W, R283H/G245SS, R213Q/Y234H, I254D, R273H | Not specified | BL-41, BL-60, CA-46, DG-75, Namalwa, Raji, Ramos, SUDHL-4, Colo320 | TRAPP recruits HATs to chromatin and increases acetylation and accumulation of mutp53 through inhibition of MDM2-mediated degradation. | [82] |
| P/CAF | R175H, G245A, D281G | K320, K373 | H1299 | Treatment of cells with TSA acetylates mutp53 at K320 and K373 by P/CAF to increase apoptosis with enhanced DNA binding of mutp53 to the p21 and PUMA promoters. | [83] |
| Id4 | P223L/V274F | K320, K373 | DU145 | Id4 increases interaction of mutp53 with CBP/p300, acetylation at K320 and K373 on mutp53, and apoptosis with upregulation of p21, BAX, and PUMA. | [84] |
| Deacetylation | |||||
| Glucose restriction | G245A | Not specified (6Q mutations in K319, K320, K321, K370, K372, K373) | H1299 | G245A-K6Q shows resistance to mutp53 degradation and cell death induced by glucose restriction. | [36] |
| SIRT1 | R249S, R273H, V157F, M237I | K382 | BT549, MDA-MB-468, HS578T, SUM149PT | Activation of SIRT1 deacetylase by YK-3-237 decreases mutp53 levels with reduced acetylation at K382, leading to induction of apoptotic cell death and G2/M cell cycle arrest with induction of wtp53 target genes. | [85] |
| Ubiquitination | |||||
| COP1, CHIP (independent of MDM2) | R175H | Not specified | U2OS, H1299, MDM2−/−TP53−/− MEFs | Downregulation of COP1 or CHIP reduces ubiquitination of mutp53 independent of MDM2. | [86] |
| Not specified/MDM2-independent ubiquitination | C135Y, V143A, H179E | Not specified | U2OS, MDM2−/−TP53−/− MEFs | Misfolded mutp53 is more efficiently ubiquitinated and localizes to the cytoplasm to a greater extent than a DNA contact mutp53 (R248W). | [87] |
| MDM2 | R273H | Not specified | H1048, H1299, WI38 | S15 phosphorylation of mutp53 by ATM following DNA damage inhibits MDM2-mediated polyubiquitination and degradation of mutp53 with allowing its monoubiquitination and accumulation. | [88] |
| MDM2 isoform B (MDM2-B) | R175H, R248W, R273H, Y220C S241F | Not specified | H1299, HCT116, T47D, Huh7, DLD-1 | MDM2-B binds to and inhibits full-length MDM2 (MDM2-FL)-mediated mutp53 degradation, leading to enhanced mutp53 GOF activities to promote tumor growth and metastasis. | [89] |
| CHIP | R156P, R175H, Y220C | Not specified | KHOS/NP, SKBR3, CAL33, BxPC3 | Cholesterol-lowering drugs “statins,” knockdown of mevalonate kinase, and DNAJA1 knockdown induce CHIP-mediated nuclear export and degradation of mainly conformational/misfolded mutp53. | [29] |
| CHIP | R110P, R175H | Not specified | HCT116, CAL33 | Aggregating TP53 mutants (R110P, R175H), but not non-aggregating mutants (R248W, R273H), are ubiquitinated and degraded by CHIP via K63-linked polyubiquitination in a manner dependent on autophagy. | [30] |
| Pirh2 | R175H, R248W, H179Y/R282W, R273H | Not specified | SW480, MiaPaCa-2, HaCaT, HCT116 | Arsenic trioxide (ATO) induces Pirh2-mediated degradation of multiple TP53 mutants. | [90] |
| Deubiquitination | |||||
| USP10 | Not specified | Not specified | 786-O | USP10 overexpression inhibits MDM2-mediated mutp53 ubiquitination leading to stabilization of mutp53 as well as increased colony formation and cell proliferation. | [91] |
| USP15 | R175H | Not specified | TYK-Nu, TOV112D, SKOV3 | MCB-613, a stimulator of steroid receptor coactivators (SRCs), enhances nuclear export, ubiquitination, and lysosome-mediated degradation of mutp53 (R175H), but not R273H, through inhibition of USP15, leading to reduced viability of ovarian cancer cells. | [92] |
| Molecular Chaperons | |||||
| HSP90 | L194F, S241F, R273C, R273H | N/A | T47D, DLD1, C33A, MDA-MB-468 | HSP90 forms a complex with MDM2 and mutp53 to block ubiquitination of both MDM2 and mutp53, while HSP90 inhibition by geldanamycin induces MDM2-mediated mutp53 degradation. | [93] |
| HSP90 | R175H, L194F, P223L/V274F, R273H, R273H/P309S, R280K, R280T | N/A | SKBR3, T47D, DU145, MDA-MB-468, MDA-MB-231, SW480, 5637 | HSP90 forms a complex with mutp53 to prevent mutp53’s aggregation by inhibiting MDM2 and CHIP activities. | [94] |
| HSP90 (HDAC6-HSP90-mutp53 complex) | R175H, L194F, P223L/V274F, S241F, R273H/P309S, R280K | N/A | SKRB3, T47D, DU145, ES2, SW480, MDA-MB-231 | Inhibition of HSP90 activity by SAHA releases mutp53 from the HDAC6-HSP90-mutp53 complex, leading to mutp53 degradation by MDM2 and CHIP to enhance cell death by a chemotherapy agent, Camptothesin. | [95] |
| HSP90 | mouse R172H and R248Q | N/A | T-lymphomas | Inhibition of HSP90 by ganetespib results in degradation of mutp53 in lymphomas and prolongs survival of TP53R172H/R172H and TP53R248Q/− mice with minimal effects on TP53-null mice. | [50] |
| HSP90 (HDAC6-HSP90-mutp53 complex) | R175H, L194F, M237I, R249S, R273H | N/A | SKBR3, T47D, SUM149, Mahlavu, BT549, MDA-MB-468 | Inhibition of the mevalonate–RhoA axis by cerivastatin or GGTI-298 reduces HDAC6 activity, leading to HSP90 hyperacetylation and dissociation of HSP90 from mutp53, which induces degradation of mutp53 by MDM2. | [51] |
| HSP70/HSC70 | R175H, R273H | N/A | MDA-MB-468, H1299 | HSP70 selectively recognizes unfolded/misfolded TP53 proteins and promotes its CHIP-dependent ubiquitination and degradation when HSP90 is inhibited and mutp53 folding is blocked. | [96] |
| HSP70 (not HSC70) | V143A, R175H | N/A | MDM2−/−TP53−/− MEFs, H1299, SKBR3 | HSP70 accelerates CHIP-mediated degradation of mutp53, whereas it partially inhibits MDM2-mediated ubiquitination and degradation of mutp53 to enhance nuclear aggregates which can be inhibited by HSC70. | [97] |
| HSC70 | R248Q, S241F, R158Inf, R280L, G266Q, S227K, S227R, E258K, A161T, R273L, R273H, R280L, R175H, R175D, R175C, R248W, R248L, R282W, P151H, P98S, G245C, L194F | N/A | OVCAR-3, ES2, SUM159, MDA-MB-231, MDA-MB-435, HCT116 | Chaperone-mediated autophagy (CMA), which is induced in cells treated with an autophagy inhibitor (spautin-1) under confluency or nutrient deprivation conditions, facilitates nuclear export of mutp53 and promotes interaction of mutp53 with HSC70, leading to mutp53 degradation through the lysosome. | [35] |
| Mortalin (mtHSP70/Grp75) | R249S | N/A | PLC/PRF/5 | Mortalin knockdown induces nuclear translocation and apoptosis in a mutp53-dependent manner. | [98] |
| Tid/DNAJA3 (HSP40) | R175H, L194F, R273H, E285K | N/A | SKBR3, T47D, U373, BT474 | Overexpression of Tid/DNAJA3 restores mitochondrial localization and pro-apoptotic activities of TP53 in cells treated with desferroxamine (DFX). | [99] |
| DNAJB1 (HSP40) | R175H | N/A | H1299, CAL-33, HuCCT1, FAMPAC, KLE, TOV112D | Chetomin (CTM) binds to HSP40 and increases the interaction between HSP40 and R175H mutp53, leading to restoration of wtp53 activity and inhibition of proliferation and tumor growth of multiple cancer cells expressing R175H with upregulation of TP53 target genes. | [57] |
| DNAJB1 (HSP40), HSP70 | V143A, R158L, R175H, Y220C, G245S, D281G, R282W | N/A | H1299 | DNAJB1 and HSP70 facilitate binding of mutp53 to TAp73α. | [100] |
| DNAJA1 (HSP40) | R156P, R175H, Y220C | N/A | KHOS/NP, SKBR3, CAL33, BxPC3 | DNAJA1 binds to and stabilizes mainly conformational or misfolded mutp53 by competitively binding to CHIP. | [29] |
| BAG2 | mouse R172H, R175H, R248W, R273H | N/A | R172H MEFs, H1299, Saos2, HCT116 | BAG2 binds to mutp53 (mouse R172H) and inhibits MDM2’s activity to accumulate mutp53, while BAG2 knockdown increases chemosensitivity and reduces tumor growth and metastasis. | [101] |
| BAG5 | mouse R172H, R175H, R248W, R273H | N/A | R172H MEFs, H1299, Saos2, HCT116 | BAG5 binds to mutp53 (mouse R172H) and inhibits ubiquitination and degradation of mutp53 by MDM2 and CHIP to accumulate mutp53 and enhance mutp53 GOF, including cell proliferation, migration, chemoresistance, and tumor growth. | [102] |
| SNP | |||||
| 72P/R polymorphism | V143A, V173L, R175H | 72P, 72R | Saos2 | 72R-mutp53 binds more efficiently to TP73 to inactivate TP73-induced apoptosis than 72P-mutp53. | [103] |
| 72P/R polymorphism | V173L, R175H, C176Y, H179R, Y220C, C242Y, G245S/D, R249S, R282W, R273C | 72P, 72R | Saos2 | 72R-mutp53 shows higher efficiency on inhibition of apoptosis induced by chemotherapy drugs, as compared to 72P-mutp53, mainly due to mutp53’s inhibitory binding with TP73. | [104] |
| 72P/R polymorphism | R249S | 72P, 72R | H1299 | Polymorphism at codon 72 in several TP53 mutants (R175H, G245S, R248W, R249S, R273H, R282W) do not show any significant differences in resistance to many chemotherapy drugs, whereas only 72R in R249S mutp53 makes cells more resistance to doxorubicin than 72P in R249S. | [105] |
| 72P/R polymorphism | R175H, R273H | 72P, 72R | H1299, PC13, HT29 (72P-R273H), SW620 (72R-R273H) | 72R-mutp53 less efficiently binds to and inhibits activity of PCG-1α, leading to higher mitochondrial function and metastatic potential than 72P-mutp53. | [106] |
| Dimer | |||||
| Mutations in the TP53 oligomerization domain | R175H, R248W | E343K | U2OS, H1299 | E343K mutation in mutp53 enhances degradation of mutp53 by MDM2, leading to inhibited migration. | [107] |