A Mutant p53-Dependent Embryonic Stem Cell Gene Signature Is Associated with Augmented Tumorigenesis of Stem Cells.

Mutations in the tumor suppressor p53 are the most frequent alterations in human cancer. These mutations include p53-inactivating mutations as well as oncogenic gain-of-function (GOF) mutations that endow p53 with capabilities to promote tumor progression. A primary challenge in cancer therapy is targeting stemness features and cancer stem cells (CSC) that account for tumor initiation, metastasis, and cancer relapse.

Various stress stimuli rewire the profile of liver secretome in a p53-dependent manner.

Liver is an important secretory organ that consistently manages various insults in order to retain whole-body homeostasis. Importantly, it was suggested that the tumor-suppressor p53 plays a role in a variety of liver physiological processes and thus it is being regarded as a systemic homeostasis regulator. Using high-throughput mass spectrometric analysis, we identified various p53-dependent liver secretome profiles.

Mutant p53 gain of function underlies high expression levels of colorectal cancer stem cells markers.

Emerging notion in carcinogenesis ascribes tumor initiation and aggressiveness to cancer stem cells (CSCs). Specifically, colorectal cancer (CRC) development was shown to be compatible with CSCs hypothesis. Mutations in p53 are highly frequent in CRC, and are known to facilitate tumor development and aggressiveness.

Dysfunctional diversity of p53 proteins in adult acute myeloid leukemia: projections on diagnostic workup and therapy.

The heterogeneous nature of acute myeloid leukemia (AML) and its poor prognosis necessitate therapeutic improvement. Current advances in AML research yield important insights regarding AML genetic, epigenetic, evolutional, and clinical diversity, all in which dysfunctional p53 plays a key role. As p53 is central to hematopoietic stem cell functions, its aberrations affect AML evolution, biology, and therapy response and usually predict poor prognosis.

p53 and its mutants on the slippery road from stemness to carcinogenesis.

Normal development, tissue homeostasis and regeneration following injury rely on the proper functions of wide repertoire of stem cells (SCs) persisting during embryonic period and throughout the adult life. Therefore, SCs employ robust mechanisms to preserve their genomic integrity and avoid heritage of mutations to their daughter cells. Importantly, propagation of SCs with faulty DNA as well as dedifferentiation of genomically altered somatic cells may result in derivation of cancer SCs, which are considered to be the driving force of the tumorigenic process.

Differential regulated microRNA by wild type and mutant p53 in induced pluripotent stem cells.

The tumour suppressor p53 plays an important role in somatic cell reprogramming. While wild-type p53 reduces reprogramming efficiency, mutant p53 exerts a gain of function activity that leads to increased reprogramming efficiency. Furthermore, induced pluripotent stem cells expressing mutant p53 lose their pluripotency in vivo and form malignant tumours when injected in mice.

Immune deficiency augments the prevalence of p53 loss of heterozygosity in spontaneous tumors but not bi-directional loss of heterozygosity in bone marrow progenitors.

p53 loss of heterozygosity (LOH) is a frequent event in tumors of somatic and Li-Fraumeni syndrome patients harboring p53 mutation. Here, we focused on resolving a possible crosstalk between the immune-system and p53 LOH. Previously, we reported that p53 heterozygous bone-marrow mesenchymal progenitor cells undergo p53 LOH in-vivo.

p53 on the crossroad between regeneration and cancer.

Regeneration and tumorigenesis share common molecular pathways, nevertheless the outcome of regeneration is life, whereas tumorigenesis leads to death. Although the process of regeneration is strictly controlled, malignant transformation is unrestrained. In this review, we discuss the involvement of TP53, the major tumor-suppressor gene, in the regeneration process.

Oncogenic Mutant p53 Gain of Function Nourishes the Vicious Cycle of Tumor Development and Cancer Stem-Cell Formation.

More than half of human tumors harbor an inactivated p53 tumor-suppressor gene. It is well accepted that mutant p53 shows an oncogenic gain-of-function (GOF) activity that facilitates the transformed phenotype of cancer cells. In addition, a growing body of evidence supports the notion that cancer stem cells comprise a seminal constituent in the initiation and progression of cancer development.

Novel p53 target genes secreted by the liver are involved in non-cell-autonomous regulation.

The tumor-suppressor p53 is a transcription factor that prevents cancer development and is involved in regulation of various physiological processes. This is mediated both by induction of cell cycle arrest and apoptosis and by controlling the expression of a plethora of target genes, including secreted proteins. It has been demonstrated that p53 may exert its effect in non-cell-autonomous manner by modulating the expression of genes that encode for secreted factors.

p53 in liver pathologies-taking the good with the bad.

The distinct physiology of the liver makes it a unique ground with respect to its cross talk with p53, the "guardian of the genome." The stressful environment in the liver frequently leads to the activation of p53, which is associated with alterations in metabolic pathways and induction of apoptosis. The latter serves as a mechanism that controls the deposal of DNA-damaged cells.

The onset of p53 loss of heterozygosity is differentially induced in various stem cell types and may involve the loss of either allele.

p53 loss of heterozygosity (p53LOH) is frequently observed in Li-Fraumeni syndrome (LFS) patients who carry a mutant (Mut) p53 germ-line mutation. Here, we focused on elucidating the link between p53LOH and tumor development in stem cells (SCs). Although adult mesenchymal stem cells (MSCs) robustly underwent p53LOH, p53LOH in induced embryonic pluripotent stem cells (iPSCs) was significantly attenuated.

Rescue of embryonic stem cells from cellular transformation by proteomic stabilization of mutant p53 and conversion into WT conformation.

p53 is a well-known tumor suppressor that is mutated in over 50% of human cancers. These mutations were shown to exhibit gain of oncogenic function compared with the deletion of the gene. Additionally, p53 has fundamental roles in differentiation and development; nevertheless, mutant p53 mice are viable and develop malignant tumors only on adulthood.

The paradigm of mutant p53-expressing cancer stem cells and drug resistance.

It is well accepted that expression of mutant p53 involves the gain of oncogenic-specific activities accentuating the malignant phenotype. Depending on the specific cancer type, mutant p53 can contribute to either the early or the late events of the multiphase process underlying the transformation of a normal cell into a cancerous one. This multifactorial system is evident in ~50% of human cancers.

p53 is required for brown adipogenic differentiation and has a protective role against diet-induced obesity.

Proper regulation of white and brown adipogenic differentiation is important for maintaining an organism's metabolic profile in a homeostatic state. The recent observations showing that the p53 tumor suppressor plays a role in metabolism raise the question of whether it is involved in the regulation of white and brown adipocyte differentiation. By using several in vitro models, representing various stages of white adipocyte differentiation, we found that p53 exerts a suppressive effect on white adipocyte differentiation in both mouse and human cells.

Epigenetic polymorphism and the stochastic formation of differentially methylated regions in normal and cancerous tissues.

DNA methylation has been comprehensively profiled in normal and cancer cells, but the dynamics that form, maintain and reprogram differentially methylated regions remain enigmatic. Here, we show that methylation patterns within populations of cells from individual somatic tissues are heterogeneous and polymorphic. Using in vitro evolution of immortalized fibroblasts for over 300 generations, we track the dynamics of polymorphic methylation at regions developing significant differential methylation on average.

p53 counteracts reprogramming by inhibiting mesenchymal-to-epithelial transition.

The process of somatic cell reprogramming is gaining increasing interest as reprogrammed cells are considered to hold a great therapeutic potential. However, with current technologies this process is relatively inefficient. Recent studies reported that inhibition of the p53 tumor suppressor profoundly facilitates reprogramming and attributed this effect to the ability of p53 to restrict proliferation and induce apoptosis.

p53, a novel regulator of lipid metabolism pathways.

Background & Aims: In this study we aimed at characterizing the regulation of hepatic metabolic pathways by the p53 transcription factor.

Methods: Analysis of gene expression following alteration of p53 status in several human- and mouse-derived cells using microarray analysis, quantitative real-time PCR, chromatin immunoprecipitation, and reporter gene assays. A functional assay was performed to determine lipid transfer activity.

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes.

Neural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear.

Mutant p53 facilitates somatic cell reprogramming and augments the malignant potential of reprogrammed cells.

p53 deficiency enhances the efficiency of somatic cell reprogramming to a pluripotent state. As p53 is usually mutated in human tumors and many mutated forms of p53 gain novel activities, we studied the influence of mutant p53 (mut-p53) on somatic cell reprogramming. Our data indicate a novel gain of function (GOF) property for mut-p53, which markedly enhanced the efficiency of the reprogramming process compared with p53 deficiency.

Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells.

A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominant-negative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53(R175H) mutant expression resulted in the upregulation of cell cycle progression genes.

p53 is balancing development, differentiation and de-differentiation to assure cancer prevention.

Many of the roles played by the tumor suppressor p53 in restraining cancer initiation and progression are well established. These include the ability of p53 to induce cell-cycle arrest, DNA repair, senescence and apoptosis. In addition, during the 30 years of p53 research, numerous studies have implicated p53 in the regulation of differentiation and developmental pathways.

p53-dependent transcriptional regulation of EDA2R and its involvement in chemotherapy-induced hair loss.

The p53 tumor suppressor coordinates a multitude of cellular and organismal processes and exerts its activities mainly by activation of gene transcription. Here we describe the transcriptional activation of ectodysplasin A2 receptor (EDA2R) by p53 in a variety of cell types and tissues. We demonstrate that treatment of cancer cells with the ligand EDA-A2, known to specifically activate EDA2R, results in p53-dependent cell death.

Prostate stromal cells produce CXCL-1, CXCL-2, CXCL-3 and IL-8 in response to epithelia-secreted IL-1.

It is well accepted that tumor microenvironment is essential for tumor cells survival, cancer progression and metastasis. However, the mechanisms by which tumor cells interact with their surrounding at early stages of cancer development are largely unidentified. The aim of this study was to identify specific molecules involved in stromal-epithelial interactions that might contribute to early stages of prostate tumor formation.