p53 orchestrates between normal differentiation and cancer

Rivlin, Noa; Koifman, Gabriela; Rotter, Varda

doi:10.1016/j.semcancer.2013.12.006

Cited by 50 publications

(45 citation statements)

References 153 publications

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“…However, the R175H GOF mutant promoted the expansion of mammary stem cells and cancer initiation ). Thus, mutant p53 appears capable of tipping the balance between pluripotency and tumor formation (Rivlin et al 2015). Consistently, the presence of TP53 mutations correlates with stem-cell-like geneexpression patterns in diverse types of cancer (Mizuno et al 2010;Villanueva and Hoshida 2011;Woo et al 2011;Schwede et al 2013).…”

Section: Emerging Areas For Clinical Applications Of Tp53 Mutation Tementioning

confidence: 70%

Clinical Outcomes of TP53 Mutations in Cancers

Robles

Jen

Harris

2016

Cold Spring Harb Perspect Med

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High-throughput sequencing of cancer genomes is increasingly becoming an essential tool of clinical oncology that facilitates target identification and targeted therapy within the context of precision medicine. The cumulative profiles of somatic mutations in cancer yielded by comprehensive molecular studies also constitute a fingerprint of historical exposures to exogenous and endogenous mutagens, providing insight into cancer evolution and etiology. Mutational signatures that were first established by inspection of the TP53 gene somatic landscape have now been confirmed and expanded by comprehensive sequencing studies. Further, the degree of granularity achieved by deep sequencing allows detection of low-abundance mutations with clinical relevance. In tumors, they represent the emergence of small aggressive clones; in normal tissues, they signal a mutagenic exposure related to cancer risk; and, in blood, they may soon become effective surveillance tools for diagnostic purposes and for monitoring of cancer prognosis and recurrence.

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Section: Emerging Areas For Clinical Applications Of Tp53 Mutation Tementioning

confidence: 70%

Clinical Outcomes of TP53 Mutations in Cancers

Robles

Jen

Harris

2016

Cold Spring Harb Perspect Med

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“…Epigenetic stress, such as global DNA methylation loss, can trigger p53-induced cell death (Jackson-Grusby et al 2001;Chiappinelli et al 2016). Although p53 knockout mice are viable, they display frequent developmental defects (Molchadsky et al 2010) along with early onset cancer (Donehower et al 1992;Rivlin et al 2015). At a young age, prior to cancer formation, p53 knockout mice display deregulation of the DNA methylation machinery (Park et al 2005).…”

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confidence: 99%

p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

et al. 2017

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DNA methylation is a key regulator of embryonic stem cell (ESC) biology, dynamically changing between naïve, primed, and differentiated states. The p53 tumor suppressor is a pivotal guardian of genomic stability, but its contributions to epigenetic regulation and stem cell biology are less explored. We report that, in naïve mouse ESCs (mESCs), p53 restricts the expression of the de novo DNA methyltransferases Dnmt3a and Dnmt3b while upregulating Tet1 and Tet2, which promote DNA demethylation. The DNA methylation imbalance in p53-deficient (p53 −/− ) mESCs is the result of augmented overall DNA methylation as well as increased methylation landscape heterogeneity. In differentiating p53−/− mESCs, elevated methylation persists, albeit more mildly. Importantly, concomitant with DNA methylation heterogeneity, p53−/− mESCs display increased cellular heterogeneity both in the "naïve" state and upon induced differentiation. This impact of p53 loss on 5-methylcytosine (5mC) heterogeneity was also evident in human ESCs and mouse embryos in vivo. Hence, p53 helps maintain DNA methylation homeostasis and clonal homogeneity, a function that may contribute to its tumor suppressor activity.[Keywords: DNA methylation; p53; stem cells] Supplemental material is available for this article. DNA methylation is a key epigenetic mark that is correlated with the major transitions during embryogenesis and other developmental processes. Differentiation and dedifferentiation of mouse embryonic stem cells (mESCs) provide a model for analyzing the regulation and possible functional roles of DNA methylation in maintaining pluripotency and facilitating differentiation. For example, when mESCs are induced to undergo differentiation, the transcriptional network ensuring pluripotency is silenced, and de novo DNA methylation is observed at promoters of key pluripotency factors (Thiagarajan et al. 2014). Conversely, when serum-maintained mESCs are moved to serum-free conditions with two kinase inhibitors (2i), their developmental potential is enhanced alongside substantial loss of DNA methylation . These transitions recapitulate early embryonic stages (Nichols and Smith 2009;Martin Gonzalez et al. 2016), but the mechanisms modulating DNA methylation remain to be fully characterized. The DNA methylation machinery is crucial for lineage specification, and mice lacking functional DNA methyltransferases (DNMTs) fail to develop properly (Siegfried and Cedar 1997;Smith and Meissner 2013); therefore, more comprehensive elucidation of the regulation of DNA methylation is pivotal to understanding the pluripotent state.In mammals, DNA methylation is governed by three DNMTs: Dnmt3a and Dnmt3b, responsible for setting de novo DNA methylation patterns, and Dnmt1, required primarily for maintenance of such patterns. In addition, TET enzymes (Tet1 and Tet2 in mESCs) facilitate demethylation by catalyzing oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), which, by sequential oxidation steps, provides the substrate for reversal to unmethylated...

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“…In view of the complexities of p53 functions in the context of embryonic development and cell differentiation (31)(32)(33)(34), it is possible that Gbx2 is not the only player in phenotypic rescue. Nevertheless, our data about the Gbx2 gene illustrate an intriguing mechanism of interaction that might function also on other target genes yet to be identified.…”

Section: Discussionmentioning

confidence: 99%

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

Caprio

Baldini

2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The 22q11.2 deletion is the most common known genetic cause of congenital heart disease (CHD). The haploinsufficiency of TBX1 has been identified as the cause of CHD. Using mouse models of the disease, we found that reduced dosage of p53 suppresses the Tbx1 mutant phenotype. Tbx1 and p53 proteins coregulate the gene Gbx2 , which is required for cardiovascular development. Gbx2 expression is positively regulated by Tbx1, whereas suppression of p53 results in reduced levels of the repressive chromatin mark H3K27me3 at a genetic element occupied by both Tbx1 and p53. These data illustrate a mechanism by which reduced p53, by genetic or pharmacological means, can counterbalance the consequences of reduced dosage of Tbx1.

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p53 orchestrates between normal differentiation and cancer

Cited by 50 publications

References 153 publications

Clinical Outcomes of TP53 Mutations in Cancers

Clinical Outcomes of TP53 Mutations in Cancers

p53 is essential for DNA methylation homeostasis in naïve embryonic stem cells, and its loss promotes clonal heterogeneity

p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome

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