The tumor suppressor protein p53 is inactivated in a large variety of cancer cells. Cellular p53 inhibitors like the mouse double minute 2 homolog (MDM2) commonly suppress the p53 function in acute myeloid leukemia (AML). Moreover, fms like tyrosine kinase 3 (FLT3) growth factor signaling pathways including the mitogen-activated kinase (MAPK) cascade (RAS-RAF-MEK-ERK) are highly active in AML cells. Consequently, the combined administration of MDM2 and MEK inhibitors may present a promising anti-leukemic treatment strategy. Here we assessed the MDM2 antagonist idasanutlin and the MEK1 inhibitor cobimetinib as single agents and in combination in a variety of AML cell lines and primary AML blast cells for their ability to induce apoptosis and cell death. AML cell lines and blast cells comprised all major AML subtypes based on the mutational status of TP53, FLT3 and NPM1 genes. We observed a considerably varying anti-leukemic efficacy of idasanutlin and cobimetinib. AML cells with high sensitivity to the single compounds as well as to the combined treatment emerged with normal karyotype, wild-type TP53 and elevated FLT3 and MDM2 protein levels. Our data indicate that AML cells with normal karyotype (NK) and wild-type status of TP53 with elevated FLT3 and MDM2 expression emerge to be most sensitive to the combined treatment with cobimetinib and idasanutlin. FLT3 and MDM2 are biomarkers for treatment response to idasanutlin and cobimetinib in AML. Full article

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer. Full article

The compound APR-246 (PRIMA-1^MET) is a known reactivator of (mutant) p53 and inducer of oxidative stress which can sensitize cancer cells to platinum-based chemotherapeutics. However, the effect of a hypoxic tumor environment has been largely overlooked in this interaction. This study focusses on the role of hypoxia-inducible factor-1α (HIF-1α) and the p53 tumor suppressor protein in hypoxia-induced cisplatin resistance in non-small cell lung cancer (NSCLC) cells and the potential of APR-246 to overcome this resistance. We observed that hypoxia-induced cisplatin resistance only occurred in the p53 mutant NCI-H2228^Q331* cell line, and not in the wild type A549 and mutant NCI-H1975^R273H cell lines. Cisplatin reduced HIF-1α protein levels in NCI-H2228^Q331* cells, leading to a shift in expression from HIF-1α-dependent to p53-dependent transcription targets under hypoxia. APR-246 was able to overcome hypoxia-induced cisplatin resistance in NCI-H2228^Q331* cells in a synergistic manner without affecting mutant p53^Q331* transcriptional activity, but significantly depleting total glutathione levels more efficiently under hypoxic conditions. Synergism was dependent on the presence of mutant p53^Q331* and the induction of reactive oxygen species, with depletion of one or the other leading to loss of synergism. Our data further support the rationale of combining APR-246 with cisplatin in NSCLC, since their synergistic interaction is retained or enforced under hypoxic conditions in the presence of mutant p53. Full article

The tumor suppressor p53 (TP53) is the most frequently mutated human gene. Mutations in TP53 not only disrupt its tumor suppressor function, but also endow oncogenic gain-of-function (GOF) activities in a manner independent of wild-type TP53 (wtp53). Mutant TP53 (mutp53) GOF is mainly mediated by its binding with other tumor suppressive or oncogenic proteins. Increasing evidence indicates that stabilization of mutp53 is crucial for its GOF activity. However, little is known about factors that alter mutp53 stability and its oncogenic GOF activities. In this review article, we primarily summarize key regulators of mutp53 stability/activities, including genotoxic stress, post-translational modifications, ubiquitin ligases, and molecular chaperones, as well as a single nucleotide polymorphism (SNP) and dimer-forming mutations in mutp53. Full article

The tumor suppressor and transcription factor p53 plays critical roles in tumor prevention by orchestrating a wide variety of cellular responses, including damaged cell apoptosis, maintenance of genomic stability, inhibition of angiogenesis, and regulation of cell metabolism and tumor microenvironment. TP53 is one of the most commonly deregulated genes in cancer. The p53-ARF-MDM2 pathway is deregulated in 84% of glioblastoma (GBM) patients and 94% of GBM cell lines. Deregulated p53 pathway components have been implicated in GBM cell invasion, migration, proliferation, evasion of apoptosis, and cancer cell stemness. These pathway components are also regulated by various microRNAs and long non-coding RNAs. TP53 mutations in GBM are mostly point mutations that lead to a high expression of a gain of function (GOF) oncogenic variants of the p53 protein. These relatively understudied GOF p53 mutants promote GBM malignancy, possibly by acting as transcription factors on a set of genes other than those regulated by wild type p53. Their expression correlates with worse prognosis, highlighting their potential importance as markers and targets for GBM therapy. Understanding mutant p53 functions led to the development of novel approaches to restore p53 activity or promote mutant p53 degradation for future GBM therapies. Full article

In this review we focus on the major isoforms of the tumor-suppressor protein p53, dysfunction of which often leads to cancer. Mutations of the TP53 gene, particularly in the DNA binding domain, have been regarded as the main cause for p53 inactivation. However, recent reports demonstrating abundance of p53 isoforms, especially the N-terminally truncated ones, in the cancerous tissues suggest their involvement in carcinogenesis. These isoforms are ∆40p53, ∆133p53, and ∆160p53 (the names indicate their respective N-terminal truncation). Due to the lack of structural and functional characterizations the modes of action of the p53 isoforms are still unclear. Owing to the deletions in the functional domains, these isoforms can either be defective in DNA binding or more susceptive to altered ‘responsive elements’ than p53. Furthermore, they may exert a ‘dominant negative effect’ or induce more aggressive cancer by the ‘gain of function’. One possible mechanism of p53 inactivation can be through tetramerization with the ∆133p53 and ∆160p53 isoforms—both lacking part of the DNA binding domain. A recent report and unpublished data from our laboratory also suggest that these isoforms may inactivate p53 by fast aggregation—possibly due to ectopic overexpression. We further discuss the evolutionary significance of the p53 isoforms. Full article

The tumor suppressor p53 is a transcriptional factor broadly mutated in cancer. Most inactivating and gain of function mutations disrupt the sequence-specific DNA binding domain, which activates target genes. This is perhaps the main reason why most research has focused on the relevance of such transcriptional activity for the prevention or elimination of cancer cells. Notwithstanding, transcriptional regulation may not be the only mechanism underlying its role in tumor suppression and therapeutic responses. In the past, a direct role of p53 in DNA repair transactions that include the regulation of homologous recombination has been suggested. More recently, the localization of p53 at replication forks has been demonstrated and the effect of p53 on nascent DNA elongation has been explored. While some data sets indicate that the regulation of ongoing replication forks by p53 may be mediated by p53 targets such as MDM2 (murine double minute 2) and polymerase (POL) eta other evidences demonstrate that p53 is capable of controlling DNA replication by directly interacting with the replisome and altering its composition. In addition to discussing such findings, this review will also analyze the impact that p53-mediated control of ongoing DNA replication has on treatment responses and tumor suppressor abilities of this important anti-oncogene. Full article

p53 has functional roles in tumor suppression as a guardian of the genome, surveillant of oncogenic cell transformation, and as recently demonstrated, a regulator of intracellular metabolism. Accumulating evidence has shown that the tumor microenvironment, accompanied by inflammation and tissue remodeling, is important for cancer proliferation, metastasis, and maintenance of cancer stem cells (CSCs) that self-renew and generate the diverse cells comprising the tumor. Furthermore, p53 has been demonstrated to inhibit inflammatory responses, and functional loss of p53 causes excessive inflammatory reactions. Moreover, the generation and maintenance of CSCs are supported by the inflammatory tumor microenvironment. Considering that the functions of p53 inhibit reprogramming of somatic cells to stem cells, p53 may have a major role in the inflammatory microenvironment as a tumor suppressor. Here, we review our current understanding of the mechanisms underlying the roles of p53 in regulation of the inflammatory microenvironment, tumor microenvironment, and tumor suppression. Full article

Viral oncogenesis is a multistep process largely depending on the complex interplay between viruses and host factors. The oncoviruses are capable of subverting the cell signaling machinery and metabolic pathways and exploit them for infection, replication, and persistence. Several viral oncoproteins are able to functionally inactivate the tumor suppressor p53, causing deregulated expression of many genes orchestrated by p53, such as those involved in apoptosis, DNA stability, and cell proliferation. The Epstein–Barr virus (EBV) BZLF1, the high-risk human papillomavirus (HPV) E6, and the hepatitis C virus (HCV) NS5 proteins have shown to directly bind to and degrade p53. The hepatitis B virus (HBV) HBx and the human T cell lymphotropic virus-1 (HTLV-1) Tax proteins inhibit p53 activity through the modulation of p300/CBP nuclear factors, while the Kaposi’s sarcoma herpesvirus (HHV8) LANA, vIRF-1 and vIRF-3 proteins have been shown to destabilize the oncosuppressor, causing a decrease in its levels in the infected cells. The large T antigen of the Merkel cell polyomavirus (MCPyV) does not bind to p53 but significantly reduces p53-dependent transcription. This review describes the main molecular mechanisms involved in the interaction between viral oncoproteins and p53-related pathways as well as in the development of therapeutic strategies targeting such interactions. Full article

Cancer research has been heavily geared towards genomic events in the development and progression of cancer. In contrast, metabolic regulation, such as aberrant metabolism in cancer, is poorly understood. Alteration in cellular metabolism was once regarded simply as a consequence of cancer rather than as playing a primary role in cancer promotion and maintenance. Resurgence of cancer metabolism research has identified critical metabolic reprogramming events within biosynthetic and bioenergetic pathways needed to fulfill the requirements of cancer cell growth and maintenance. The tumor suppressor protein p53 is emerging as a key regulator of metabolic processes and metabolic reprogramming in cancer cells—balancing the pendulum between cell death and survival. This review provides an overview of the classical and emerging non-classical tumor suppressor roles of p53 in regulating mitochondrial dynamics: mitochondrial engagement in cell death processes in the prevention of cancer. On the other hand, we discuss p53 as a key metabolic switch in cellular function and survival. The focus is then on the conceivable roles of p53 in breast cancer metabolism. Understanding the metabolic functions of p53 within breast cancer metabolism will, in due course, reveal critical metabolic hotspots that cancers advantageously re-engineer for sustenance. Illustration of these events will pave the way for finding novel therapeutics that target cancer metabolism and serve to overcome the breast cancer burden. Full article

p53 missense mutant alleles are present in nearly 40% of all human tumors. Such mutated alleles generate aberrant proteins that not only lose their tumor-suppressive functions but also frequently act as driver oncogenes, which promote malignant progression, invasion, metastasis, and chemoresistance, leading to reduced survival in patients and mice. Notably, these oncogenic gain-of-function (GOF) missense mutant p53 proteins (mutp53) are constitutively and tumor-specific stabilised. This stabilisation is one key pre-requisite for their GOF and is largely due to mutp53 protection from the E3 ubiquitin ligases Mdm2 and CHIP by the HSP90/HDAC6 chaperone machinery. Recent mouse models provide convincing evidence that tumors with highly stabilized GOF mutp53 proteins depend on them for growth, maintenance, and metastasis, thus creating exploitable tumor-specific vulnerabilities that markedly increase lifespan if intercepted. This identifies mutp53 as a promising cancer-specific drug target. This review discusses direct mutp53 protein-targeting drug strategies that are currently being developed at various preclinical levels. Full article

The hsa-mir-483 gene, located within the IGF2 locus, transcribes for two mature microRNAs, miR-483-5p and miR-483-3p. This gene, whose regulation is mediated by the the CTNNB1/USF1 complex, shows an independent expression from its host gene IGF2. The miR-483-3p affects the Wnt/β-catenin, the TGF-β, and the TP53 signaling pathways by targeting several genes as CTNNB1, SMAD4, IGF1, and BBC3. Accordingly, miR-483-3p is associated with various tissues specific physiological properties as insulin and melanin production, as well as with cellular physiological functions such as wounding, differentiation, proliferation, and survival. Deregulation of miR-483-3p is observed in different types of cancer, and its overexpression can inhibit the pro-apoptotic pathway induced by the TP53 target effectors. As a result, the oncogenic characteristics of miR-483-3p are linked to the effect of some of the most relevant cancer-related genes, TP53 and CTNNB1, as well as to one of the most important cancer hallmark: the aberrant glucose metabolism of tumor cells. In this review, we summarize the recent findings regarding the miR-483-3p, to elucidate its functional role in physiological and pathological contexts, focusing overall on its involvement in cancer and in the TP53 pathway. Full article

The discovery of the tumor suppressor p53, through its interactions with proteins of tumor-promoting viruses, paved the way to the understanding of p53 roles in tumor virology. Over the years, accumulating data suggest that WTp53 is involved in the viral life cycle of non-tumor-promoting viruses as well. These include the influenza virus, smallpox and vaccinia viruses, the Zika virus, West Nile virus, Japanese encephalitis virus, Human Immunodeficiency Virus Type 1, Human herpes simplex virus-1, and more. Viruses have learned to manipulate WTp53 through different strategies to improve their replication and spreading in a stage-specific, bidirectional way. While some viruses require active WTp53 for efficient viral replication, others require reduction/inhibition of WTp53 activity. A better understanding of WTp53 functionality in viral life may offer new future clinical approaches, based on WTp53 manipulation, for viral infections. Full article

Following the event of DNA damage, the level of tumour suppressor protein p53 increases inducing either cell cycle arrest or apoptosis. Junctional Mediating and Regulating Y protein (JMY) is a transcription co-factor involved in p53 regulation. In event of DNA damage, JMY levels also upregulate in the nucleus where JMY forms a co-activator complex with p300/CREB-binding protein (p300/CBP), Apoptosis-stimulating protein of p53 (ASPP) and Stress responsive activator of p53 (Strap). This co-activator complex then binds to and increases the ability of p53 to induce transcription of proteins triggering apoptosis but not cell cycle arrest. This then suggests that the increase of JMY levels due to DNA damage putatively “directs” p53 activity toward triggering apoptosis. JMY expression is also linked to increased cell motility as it: (1) downregulates the expression of adhesion molecules of the Cadherin family and (2) induces actin nucleation, making cells less adhesive and more mobile, favouring metastasis. All these characteristics taken together imply that JMY possesses both tumour suppressive and tumour metastasis promoting capabilities. Full article

“Lactation is at one point perilously near becoming a cancerous process if it is at all arrested”, Beatson, 1896. Most breast cancers arise from the milk-producing cells that are characterized by aberrant cellular, molecular, and epigenetic translation. By understanding the underlying molecular disruptions leading to the origin of cancer, we might be able to design novel strategies for more efficacious treatments or, ambitiously, divert the cancerous process. It is an established reality that full-term pregnancy in a young woman provides a lifetime reduction in breast cancer risk, whereas delay in full-term pregnancy increases short-term breast cancer risk and the probability of latent breast cancer development. Hormonal activation of the p53 protein (encode by the TP53 gene) in the mammary gland at a critical time in pregnancy has been identified as one of the most important determinants of whether the mammary gland develops latent breast cancer. This review discusses what is known about the protective influence of female hormones in young parous women, with a specific focus on the opportune role of wild-type p53 reprogramming in mammary cell differentiation. The importance of p53 as a protector or perpetrator in hormone-dependent breast cancer, resistance to treatment, and recurrence is also explored. Full article

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as “reactivating” mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells’ response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials. Full article

In addition to its classical roles as a tumor suppressor, p53 has also been shown to act as a guardian of epithelial integrity by inducing the microRNAs that target transcriptional factors driving epithelial–mesenchymal transition. On the other hand, the ENCODE project demonstrated an enrichment of putative motifs for the binding of p53 in epithelial-specific enhancers, such as CDH1 (encoding E-cadherin) enhancers although its biological significance remained unknown. Recently, we identified two novel modes of epithelial integrity (i.e., maintenance of CDH1 expression): one involves the binding of p53 to a CDH1 enhancer region and the other does not. In the former, the binding of p53 is necessary to maintain permissive histone modifications around the CDH1 transcription start site, whereas in the latter, p53 does not bind to this region nor affect histone modifications. Furthermore, these mechanisms likely coexisted within the same tissue. Thus, the mechanisms involved in epithelial integrity appear to be much more complex than previously thought. In this review, we describe our findings, which may instigate further experimental scrutiny towards understanding the whole picture of epithelial integrity as well as the related complex asymmetrical functions of p53. Such understanding will be important not only for cancer biology but also for the safety of regenerative medicine. Full article

p53 is a tumor suppressor protein. Under stressful conditions, p53 tightly regulates cell growth by promoting apoptosis and DNA repair. When p53 becomes mutated, it loses its function, resulting in abnormal cell proliferation and tumor progression. Depending on the p53 mutation, it has been shown to form aggregates leading to negative gain of function of the protein. p53 mutant associated aggregation has been observed in several cancer tissues and has been shown to promote tumor growth. Recent studies show correlation between p53 mutant aggregation, functional loss, and tumor growth. Moreover, p53 aggregation has been observed in biopsies, patient tissues, and in vivo studies. Given the fact that over fifty percent of cancers have p53 mutation and several of them are prone to aggregation, therapeutic strategies are needed for treating p53 mutant aggregation associated cancers. Recent studies using polyarginine analogues and designer peptides for inhibiting p53 aggregation and tumor growth gives further encouragement in treating cancer as a protein aggregation disease. In this review, we highlight the recent efforts in targeting p53 aggregation in cancer and propose the use of small stress molecules as potential p53-antiaggregation drugs. Full article

Since its discovery in 1979, p53 has shown multiple facets. Initially the tumor suppressor p53 protein was considered as a stress sensor able to maintain the genome integrity by regulating transcription of genes involved in cell cycle arrest, apoptosis and DNA repair. However, it rapidly came into light that p53 regulates gene expression to control a wider range of biological processes allowing rapid cell adaptation to environmental context. Among them, those related to cancer have been extensively documented. In addition to its role as transcription factor, scattered studies reported that p53 regulates miRNA processing, modulates protein activity by direct interaction or exhibits RNA-binding activity, thus suggesting a role of p53 in regulating several layers of gene expression not restricted to transcription. After 40 years of research, it appears more and more clearly that p53 is strongly implicated in translational regulation as well as in the control of the production and activity of the translational machinery. Translation control of specific mRNAs could provide yet unsuspected capabilities to this well-known guardian of the genome. Full article

The tumor suppressor p53 as the “guardian of the genome” plays an essential role in numerous signaling pathways that control the cell cycle, cell death and in maintaining the integrity of the human genome. p53, depending on the intracellular localization, contributes to the regulation of various cell death pathways, including apoptosis, autophagy and necroptosis. Accumulated evidence suggests that this function of p53 is closely involved in the process of cancer development. Here, present knowledge concerning a p53-autophagy-metastasis link, as well as therapeutic approaches that influence this link, are discussed. Full article

The p53 protein has been extensively studied for its capacity to prevent proliferation of cells with a damaged genome. Surprisingly, however, our recent analysis of mice expressing a hyperactive mutant p53 that lacks the C-terminal domain revealed that increased p53 activity may alter genome maintenance. We showed that p53 downregulates genes essential for telomere metabolism, DNA repair, and centromere structure and that a sustained p53 activity leads to phenotypic traits associated with dyskeratosis congenita and Fanconi anemia. This downregulation is largely conserved in human cells, which suggests that our findings could be relevant to better understand processes involved in bone marrow failure as well as aging and tumor suppression. Full article

TP53 is universally recognized as a pivotal protein in cell-cycle fate and apoptotic induction and, unsurprisingly, it is one of the most commonly hijacked control mechanisms in cancer. Recently, the kinase MKK3 emerged as a potential therapeutic target in different types of solid tumor being linked to mutant p53 gain-of-function. In this review, we summarize the delicate relationship among p53 mutational status, MKK3/MKK6 and the downstream activated master kinase p38MAPK, dissecting a finely-tuned crosstalk, in a potentially cell-context dependent scenario that urges towards a deeper characterization of the different molecular players involved in this signaling cascade and their interactions. Full article

p53 protects cells from genetic assaults by triggering cell-cycle arrest and apoptosis. Inactivation of p53 pathway is found in the vast majority of human cancers often due to somatic missense mutations in TP53 or to an excessive degradation of the protein. Accordingly, reactivation of p53 appears as a quite promising pharmacological approach and, effectively, several attempts have been made in that sense. The most widely investigated compounds for this purpose are PRIMA-1 (p53 reactivation and induction of massive apoptosis )and PRIMA-1^Met (APR-246), that are at an advanced stage of development, with several clinical trials in progress. Based on publications referenced in PubMed since 2002, here we review the reported effects of these compounds on cancer cells, with a specific focus on their ability of p53 reactivation, an overview of their unexpected anti-cancer effects, and a presentation of the investigated drug combinations. Full article

The translation of mRNAs plays a critical role in the regulation of gene expression and therefore, in the regulation of cell proliferation, differentiation and apoptosis. Unrestricted initiation of translation causes malignant transformation and plays a key role in the maintenance and progression of cancers. Translation initiation is regulated by the ternary complex and the eukaryotic initiation factor 4F (eIF4F) complex. The p53 tumor suppressor protein is the most well studied mammalian transcription factor that mediates a variety of anti-proliferative processes. Post-transcriptional mechanisms of gene expression in general and those of translation in particular play a major role in shaping the protein composition of the cell. The p53 protein regulates transcription and controls eIF4F, the ternary complex and the synthesis of ribosomal components, including the down-regulation of rRNA genes. In summary, the induction of p53 regulates protein synthesis and translational control to inhibit cell growth. Full article