What happens if p53 is mutated

Tumour-associated mutant p53 drives the Warburg effect. Nat Commun 4 Mutant p53 uses p63 as a molecular chaperone to alter gene expression and induce a pro-invasive secretome. Oncotarget 2 12 — Mol Cell Biol 31 — Targeting TopBP1 at a convergent point of multiple oncogenic pathways for cancer therapy. Nat Commun 5 Various p53 mutant proteins differently regulate the Ras circuit to induce a cancer-related gene signature. J Cell Sci — Nat Cell Biol 16 — YAP enhances the pro-proliferative transcriptional activity of mutant p53 proteins.

EMBO Rep Google Scholar. Mutant p53 disrupts MCFA cell polarity in three-dimensional culture via epithelial-to-mesenchymal transitions. Mutant p53 gain of function: reduction of tumor malignancy of human cancer cell lines through abrogation of mutant p53 expression. Oncogene 25 —9. Mutant conformation of p53 translated in vitro or in vivo requires functional HSP Geldanamycin selectively destabilizes and conformationally alters mutated p Oncogene 11 —9.

PubMed Abstract Google Scholar. Dasgupta G, Momand J. Geldanamycin prevents nuclear translocation of mutant p Exp Cell Res — Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment.

Nature —6. Cell Death Differ 18 12 — Histone deacetylase inhibitors suppress mutant p53 transcription via histone deacetylase 8. Oncogene 32 — Active Pin1 is a key target of all-trans retinoic acid in acute promyelocytic leukemia and breast cancer. Nat Med 21 — Restoration of the growth suppression function of mutant p53 by a synthetic peptide derived from the p53 C-terminal domain. Nat Med 3 —8. A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants.

Peptide aptamers targeting mutant p53 induce apoptosis in tumor cells. Cancer Res 68 —8. Pharmacological rescue of mutant p53 conformation and function.

CP prevents the growth of pmutated colorectal cancer cells in vitro and in vivo. Tumour Biol 36 — Biochem Biophys Res Commun — Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound.

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Nucleic Acids Res 41 — Disarming mutant p53 oncogenic function. Pharmacol Res 79 — A gene that has been coined "the guardian of the genome," when inactivated, it can also play a role in the persistence, growth, and spread of a cancer that develops.

Learn more below about the functions of TP53, how it works to stop cancer from forming, how is may be damaged, and therapies that may help to reactivate its effect. There are two types of genes that are important in the development and growth of cancers: oncogenes and tumor-suppressor genes. Most often, an accumulation of mutations in both oncogenes and tumor-suppressor genes is responsible for the development of cancer.

Oncogenes arise when normal genes present in the body proto-oncogenes are mutated, causing them to be activated continually turned on. These genes code for proteins that control cell division. Their activation might be thought of as analogous to having the accelerator stuck in the down position in a car. Tumor-suppressor genes , in contrast, code for proteins that function to repair damaged DNA so a cell can't become a cancer cell , or result in the death programmed cell death or apoptosis of cells that can't be repaired so they can't become a cancer cell.

They may also have other functions important in cancer growth, such as playing a role in regulating cell division or angiogenesis the growth of new blood vessels to feed a tumor. Using the analogy above, tumor-suppressor genes can be thought of as the brakes on a car. Tumor-suppressor genes that many people are familiar with are the BRCA genes.

BRCA gene mutations are known to be associated with the development of breast cancer and other tumors. When the damage in DNA is too extensive to be repaired, TP53 proteins signal cells to undergo programmed cell death apoptosis.

Gain of Function. These are referred to as "gain-of-functions. A very simplistic way to look at the TP53 gene would be to picture yourself as the TP53 gene, and a plumber as one of the proteins you can control.

The plumber could then come to your home and either repair the leaky faucet, or you could remove it completely to stop the water leak. If you were unable to make the call analogous to a faulty TP53 gene , the plumber would not be called, and the leak would continue analogous to cancer cells dividing. In addition, you would not be able to turn off the water, which would eventually flood your home. Once your home is flooding, the faucet may then take on a life of its own, preventing you from turning it off, preventing other plumbers from getting near, speeding up the flow of water, and adding new leaky pipes around your home, including some that aren't even connected to the initial leaky faucet.

There are two primary types of gene mutations: germline and somatic. Germline mutations heritable mutations are the type of mutations people may be concerned with when wondering if they have a genetic predisposition to cancer.

The mutations are present from birth and affect every cell in the body. Genetic tests are now available that check for several germline mutations that increase cancer risk, such as mutated BRCA genes. Germline mutations in the TP53 gene are uncommon and associated with a specific cancer syndrome known as Li-Fraumeni syndrome.

People with Li-Fraumeni syndrome often develop cancer as children or young adults, and the germline mutation is associated with a high lifetime risk of cancers, such as breast cancer, bone cancer, muscle cancer, and more.

Somatic mutations acquired mutations are not present from birth but arise in the process of a cell becoming a cancer cell. Oncogene 22 56 — EMBO J 11 4 — Cancer Cell 10 3 — Cell Cycle 12 12 —5. Circadian variations of clock gene Per2 and cell cycle genes in different stages of carcinogenesis in golden hamster buccal mucosa.

Sci Rep 5 Nat Commun 4 EMBO J 31 6 — J Biol Chem 8 — Sahar S, Sassone-Corsi P. Metabolism and cancer: the circadian clock connection. Nat Rev Cancer 9 12 — Cell Death Differ 19 3 — Loss of PML cooperates with mutant p53 to drive more aggressive cancers in a gender-dependent manner.

Cell Cycle 12 11 — Melatonin resynchronizes dysregulated circadian rhythm circuitry in human prostate cancer cells. J Pineal Res 49 1 —8. Yin Y, Shen WH. PTEN: a new guardian of the genome. Oncogene 27 41 — PTEN tumor suppressor regulates p53 protein levels and activity through phosphatase-dependent and -independent mechanisms.

Cancer Cell 3 2 — PTEN has tumor-promoting properties in the setting of gain-of-function p53 mutations.

Cancer Res 68 6 — Regulation of PTEN transcription by p Mol Cell 8 2 — Neoplasia 15 8 — Mol Cell Biol 23 16 — Mutant p53 oncogenic functions are sustained by Plk2 kinase through an autoregulatory feedback loop. Cell Cycle 10 24 — Haupt S, Haupt Y. Mutant p53 subverts PLK2 function in a novel, reinforced loop of corruption. Cell Cycle 11 2 —8. Regulation of nucleotide metabolism by mutant p53 contributes to its gain-of-function activities. Nat Commun 6 Gottlieb E, Vousden KH.

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J Cancer Res Clin Oncol 9 — Nat Cell Biol 13 3 —6. Tumour-associated mutant p53 drives the Warburg effect. Dietary downregulation of mutant p53 levels via glucose restriction: mechanisms and implications for tumor therapy. Cell Cycle 11 23 — Beyond weight loss: a review of the therapeutic uses of very-low-carbohydrate ketogenic diets. Eur J Clin Nutr 67 8 — Metformin in cancer treatment and prevention.

Annu Rev Med 66 — SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 9 — J Biol Chem 28 — Mutant p53 disrupts mammary tissue architecture via the mevalonate pathway. Nutrient limitations represent a major point of vulnerability of cancer cells. Interestingly, nutrient availability also appears to be relevant for mutp53 accumulation in tumors, as reduced glucose levels induce autophagy-dependent mutp53 proteolysis [ 25 ].

Of note, a dietary regimen of glucose restriction reduced mutp53 accumulation in mutp53 AV knock-in mice and reduced growth of mutpexpressing tumor xenografts [ 25 ]. Multiple cancer-related stress stimuli trigger post-translational modifications of mutp53 to modulate its protein stability and interactions reviewed in ref.

For instance, constitutive activation of DNA damage checkpoint and consequent phosphorylation of Ser15 by ataxia-telangiectasia mutated ATM kinase drive stabilization of mutp53 by shifting the balance between its mono- and poly-ubiquitination [ 27 ]. This is consistent with the evidence that expression of Ras and Myc oncogenes as well as exposure to radiation- and chemotherapy-related genotoxic and oxidative stress induce accumulation of mutp53 in vivo [ 16 ].

Similarly, acetylation of C-terminal lysines has been shown to protect mutp53 from autophagy-mediated degradation [ 25 ]. Pin1 has also been implicated in supporting gain-of-function of the pRS mutant, frequently detected in human hepatocellular carcinoma HCC associated to dietary exposure to aflatoxin B1 and hepatitis B infection. Moreover, cell metabolism is a central hub interconnecting the microenvironment, cell signaling and the epigenetic landscape, and is therefore crucial for cancer cells to cope with their changing environment [ 32 ].

Not surprisingly, cell metabolism is affected by multiple oncogenic conditions, including expression of mutp One widespread metabolic adaptation of cancer cells is represented by increased glucose uptake accompanied by aerobic glycolysis known as Warburg effect , which feeds tumor growth in hypoxic conditions and contributes to suppress immune surveillance through extracellular acidification [ 33 ]. Tumors hence display extremely high glucose requirements in face of nutrient scarcity and inadequate vascular supply Fig.

Mutp53 has been reported to sustain glucose intake and hence the Warburg effect in tumor cells and knock-in mice, by the ability to induce membrane translocation of the glucose transporter GLUT1 via activation of the RhoA-ROCK axis [ 34 ] Fig.

Remarkably, by promoting glucose intake in cancer cells, mutp53 also inhibits its own autophagy-dependent proteolysis, caused by glucose deprivation [ 25 ]. In addition, in response to energy stress mutp53 can induce aerobic glycolysis by directly inhibiting AMP-activated protein kinase AMPK [ 35 ].

Depending on the specific context, mutp53 can also promote oxidative phosphorylation, as shown in pre-neoplastic thymus and spleen of Li-Fraumeni LF mouse models and in muscles of LF patients [ 36 ]. In contrast to the classic Warburg view, it has become evident that tumors display a significant degree of metabolic heterogeneity, and cancer cells can indeed activate either glycolytic or oxidative metabolism under different environmental conditions [ 8 ].

For instance, slowly proliferating tumor cells e. It is conceivable that mutp53 may endow cancer cells with metabolic plasticity, thus favoring their adaptation to metabolic stress and increasing their metastatic potential. Of note, a mutp53 R72 variant was recently shown to increase metastatic capability by stimulating mitochondrial function [ 39 ].

Many solid tumors undergo alterations of lipid metabolism, which contribute to cancer in multiple ways, e. Synergistic interaction of mutp53 with SREBPs, master regulators of fatty acids and cholesterol biosynthesis, leads to transcriptional induction of the mevalonate pathway MVP [ 42 ]. The MVP produces sterols and isoprenoids required for synthesis of membranes and lipid rafts, signal transduction and protein prenylation [ 41 ]. High levels of oxidative stress are frequently encountered during transformation as a consequence of genetic, metabolic and microenvironmental alterations, and preventing excess damage due to ROS accumulation is essential for cancer cytoprotection.

The transcription factor NRF2 is central to control key components of endogenous antioxidant systems. Very recently, our group demonstrated that missense mutp53 interacts with NRF2 and contributes to selectively activating or repressing specific components of its transcriptional program, thereby promoting a pro-survival oxidative stress response that allows cancer cells to cope with high levels of intracellular ROS [ 45 ]. The mutpactivated NRF2 target gene signature is associated with poor patient prognosis in breast cancer, and includes genes with pro-survival function, such as thioredoxin TXN ; in contrast, mutp53 represses other NRF2 targets including heme oxygenase 1 HMOX1 , which have been shown to display cytotoxic effects in cancer cells, although being cytoprotective in untransformed cells [ 46 ].

As a consequence of oxidative stress, DNA hyper-replication and telomere shortening, tumor cells endure persistent DNA lesions, leading to chronic activation of the DNA damage response DDR , a tumor suppressive barrier that eliminates incipient cancer cells through either senescence or apoptosis [ 47 ].

Moreover, chemotherapy drugs represent major genotoxic stressors for tumor cells. Interestingly, a proteomic analysis unveiled that mutp53 stimulates chromatin association and nuclear activity of PARP1, resulting in increased poly-ADP-ribosylated targets [ 50 ]. It is conceivable that, while blocking DDR activation on one hand, on the other hand mutp53 stimulates PARP function as a stress support mechanism allowing tumor cell survival in face of high levels of DNA damage.

These activities likely underlie also mutpdependent adaptive responses promoting chemotherapy and radiotherapy resistance in tumor cells. In addition, p53 mutants have been shown to boost HR-mediated DNA repair by enhancing topoisomerase 1 Top1 function, although this activity has been reported to result in hyper-recombination and genomic instability [ 51 ]. Indeed, mutp53 has been recently shown to increase DNA replication origin firing and to stabilize replication forks, thus facilitating the proliferation of cells with genomic abnormalities.

Consistently, mutp53 depletion leads to increased fork collapse in transformed cells [ 52 ]. Other adaptive mechanisms to proliferation-related stress may derive from DNA damage-induced association of mutp53 with DNA topoisomerase 2-binding protein 1 TopBP1 [ 53 ], a scaffold protein that modulates DNA damage checkpoint, DNA replication and transcription [ 54 ].

Finally, mutp53 promotes cancer cell survival under tumor- and therapy-associated stress conditions by inhibiting the apoptotic and autophagic responses.

In addition to promoting autophagy resistance through cytoplasmic activities [ 59 ], inhibition of autophagy-related ATG12 gene by mutp53 has also been reported [ 58 ]. Of note, counteracting autophagy also protects mutp53 from proteolysis [ 60 ] Fig. Adaptation to hypoxic conditions is a critical factor for tumor evolution. The cellular response to hypoxia is mainly regulated by the hypoxia inducible factor-1 HIF This is consistent with the reported ability of mutp53 to inhibit the anti-metastatic p63 target gene Sharp1 [ 62 ], a factor that promotes ubiquitin-mediated degradation of HIF and blunts HIF-induced malignant cell behavior.

Proteotoxic stress in tumor cells arises as a consequence of enhanced protein synthesis and of gene mutations, including copy number alterations that change the stoichiometry of protein-complexes, and point mutations giving rise to aberrant peptides.

All these events pose a high burden on the protein folding and degradation machineries of proliferating cancer cells. Accumulation of misfolded proteins in the ER activates the unfolded protein response UPR , a conserved transcriptional program that helps resolve protein stress, but can also trigger apoptosis [ 63 ].

Cancer cells must therefore develop mechanisms that favor adaptation to protein stress, and limit apoptotic outcomes of pathways triggered by accumulation of unfolded proteins. Various experimental evidences suggests that mutp53 has a role in this process Fig. Mutant p53 facilitates adaptation to proteotoxic stress by multiple mechanisms. At the same time, increased proteasome activity contributes to alleviate stress caused by accumulation of misfolded proteins.

The first such evidence is that mutp53 enhances activity of the proteasome. More recently, in triple-negative breast cancer TNBC cell lines, we established that proteasome upregulation is in fact a highly conserved feature of oncogenic p53 mutants, correlating with enhanced protein degradation [ 66 ].

Mechanistically, this depends on the ability of mutp53 to interact with the transcription factor NRF2, and to selectively stimulate NRF2-dependent upregulation of proteasome subunit genes. The resulting enhanced proteasome activity in cancer cells bearing mutp53 increases their fitness and aggressiveness by accelerating the turnover of oncosuppressors such as CDK inhibitors or pro-apoptotic proteins, but also by enhancing resistance to proteotoxic stress.

Of note, an augmented protein degradation capacity, associated to efficient elimination of misfolded nuclear and cytoplasmic proteins, was recently shown to be instrumental for transformation in various cell models. The second evidence is that mutp53 upregulates Heat-shock proteins Hsp. Li et al. Accordingly, cancer cell lines with mutp53 are more resistant to proteotoxic stress induced by heat shock, but also by proteasome inhibitors [ 14 ].

Moreover, HSF1-dependent accumulation of Hsps concurs to mutp53 stabilization in tumor cells [ 14 ], disclosing another feed-forward circuit instigated by mutp Thus, the interaction between mutp53 and HSF1 helps cancer cells to cope with proteotoxic stress on two fronts: by stimulating adaptation and by preventing apoptosis. Finally, recent work associated mutp53 to the folding of glycoproteins in the ER [ 69 ].

Data suggest that maturation and processing of glycoproteins in the ER is fundamental for mutp53 oncogenic activity; the pro-tumorigenic effect of this process may be due to enhanced expression of membrane receptors, but also to enhanced secretion of extracellular mediators. This observation provides a first evidence that mutp53 may favor the folding of secreted and membrane proteins in the endoplasmic reticulum, possibly also contributing to alleviate the cytostatic effects of ER stress Fig.

Most tumors grow under a strong selective pressure from the surrounding environment. In particular during the invasion-metastasis process, cancer cells face stress conditions such as matrix detachment, interaction with altered stromal components, shear mechanical forces, and the presence of an anti-tumor immune response.

The ability of cancer cells to actively shape a permissive microenvironment is thus crucial for cancer progression. Increasing evidence indicates that mutp53 can remodel the tumor microenvironment, enhancing cancer cell adaptation to hostile extracellular conditions.

First of all, mutp53 can stimulate tumor neo-angiogenesis. An old study showed that mutp53 overexpression induced VEGF in mouse fibroblasts [ 71 ]. Similarly, expression of mutp53 in bone marrow stromal cells increased production and secretion of VEGF, supporting the growth of leukemic cells [ 72 ].

Indeed, p53 mutation and VEGF levels are significantly correlated, at least in breast cancer [ 73 ]. Cancer cells secrete a variety of molecules that foster tumor growth and reseeding, and reshape the local microenvironment to facilitate invasion and metastatic dissemination. Analysis of mutpdependent tumor cell secretomes has suggested that mutpdriven oncogenicity may act via regulating the expression of secreted proteins that function in either autocrine or paracrine signaling to induce migration and invasion of tumor cells [ 75 ].

Among these alpha-1 antitrypsin A1AT was identified as a critical effector of mutp53 in driving lung cancer invasion in vitro and in vivo, and correlated with adverse prognosis in mutpexpressing lung adenocarcinoma patients [ 76 ]. Another feature of solid tumors is the presence of abundant inflammatory molecules secreted by cancer cells and by infiltrating immune cells.

Thus, cancer cells must adapt to chronic inflammation by cutting the pro-apoptotic circuits, and amplifying the pro-survival and pro-migratory inputs of inflammatory signals. In this respect, mutp53 actively reshapes the profile of cytokines and chemokines secreted by cancer cells, contributing to establish a homeostatic microenvironment that eventually supports cancer cell growth and dissemination.

For instance, mutp53 was reported to induce CXCL5, CXCL8, and CXCL12, correlating with increased cell migration and invasion, thus confirming that secretion of pro-angiogenic factors and chemokines is a gain-of-function of mutp53 [ 77 ].

As a consequence, TNF stimulation of TNBC cells with mutp53 fails to induce apoptosis, but enhances cell migration and invasion [ 82 ]. Indeed, expression of mutp53 dramatically increased the incidence of invasive colon carcinoma in a mouse model of chronic colitis [ 79 ].

It appears that p53 mutation can also protect cancer cells from anti-tumor signals produced by other cell populations in the microenvironment. For instance, in vitro studies based on co-culture suggest that mutp53 protects cells from tumor-suppressive IFN-beta secreted by cancer associated fibroblasts CAFs , enhancing survival, proliferation, and migration of lung carcinoma cell lines [ 83 ].

Finally, this concept might be extended even further, as we observed that a TNBC cell line expressing p53 RK , when exposed to TNF, secretes chemokines that modulate recruitment of immune cells to the tumor [ 82 ].

More recently, it has been shown that mutpexpressing cancers reprogram macrophages to a tumor supporting and anti-inflammatory state via exosomal secretion of miR [ 84 ]. These observations, suggesting that mutp53 could shape the tumor immune infiltrate, deserve further studies for their potential clinical implications. There is ample experimental evidence showing that interference with mutp53 expression or activity by RNAi or pharmacological approaches leads to decreased cancer cell proliferation, survival and metastasis, and even causes tumor regression in vivo reviewed in refs.

Given the uniquely high incidence of missense TP53 mutations across many different tumor types, strategies aimed at blocking mutp53 would be expected to produce a huge impact on cancer treatment. These could become treatments of choice for tumors characterized by high TP53 mutation rate and that still lack targeted therapeutic options, such as triple negative breast cancer and ovarian cancer.

A schematic view of therapeutic opportunities targeting mutp53 and the homeostatic mechanisms it coordinates in cancer cells.

PRIMA-1 is paradigmatic of small molecule compounds restoring mutp53 to its wild-type conformation and leading to its degradation.