Mutant p53 in cell-cell interactions

Pilley, Steven E.; Rodríguez, Tristan A.; Vousden, Karen H.

doi:10.1101/gad.347542.120

Cited by 30 publications

(32 citation statements)

References 162 publications

(178 reference statements)

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“…The cyclin dependant kinase inhibitor Cdkn1a ( p21) is an important target activated by P53 (Pilley et al, 2021). To test if P21 regulation of the cell cycle is an important part of the mechanism by which P53 confers a super-competitor status we generated p21 mutant ESCs (Fig.…”

Section: Resultsmentioning

confidence: 99%

Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

Montero

Bowling

Pérez-Carrasco

et al. 2022

Preprint

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During development, the rate of tissue growth is determined by the relative balance of cell division and cell death. Cell competition is a fitness quality control mechanism that contributes to this balance by eliminating viable cells that are less-fit than their neighbours. What mutations confer cells with a competitive advantage or the dynamics of the interactions between winner and loser cells are not well understood. Here, we show that embryonic cells lacking the tumour suppressor p53 are super-competitors that eliminate their wild-type neighbours through the direct induction of apoptosis. This elimination is context dependant, as does not occur when cells are pluripotent and is triggered by the onset of differentiation. Furthermore, by combining mathematical modelling and cell-based assays we show that the elimination of wild-type cells is not through a competition for space or nutrients, but instead is mediated by short range interactions that are dependent on the local cell neighbourhood. This highlights the importance of the local cell neighbourhood and the competitive interactions within this neighbourhood for the regulation of proliferation during early embryonic development.

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Section: Resultsmentioning

confidence: 99%

Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

Montero

Bowling

Pérez-Carrasco

et al. 2022

Preprint

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“…80% of the TP53‐inactivating events is observed as missense mutations underlying expression of neomorphic gain‐of‐function mutants [ 3 ]; more specifically, the largest majority of mutations generally impinge on arginine 273 (R273) or 175 (R175) and 248 (R248) (Fig. 1D , Fig.…”

Section: Resultsmentioning

confidence: 99%

“…While p53 is virtually mutated in every second human cancer, the progression of certain tumour types, including pancreatic ductal adenocarcinoma (PDAC), specifically relies on genetic alteration in TP53 gene [ 1 ]. These mutations often generate neomorphic forms of p53 protein, whose gain‐of‐function (GOF) effects seem to display a high degree of context dependency [ 2 , 3 ]; for example, in different gut microbiome environment p53 R172H can exert tumour suppressive or oncogenic functions [ 4 , 5 ]. Several mechanisms have been suggested to explain mutant p53 GOF: these include interaction with p53 family members [ 6 , 7 ], alteration in the activity of wild‐type p53 partner transcriptional factors [ 8 , 9 , 10 ] and acquisition of novel binding partners [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer

et al. 2022

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Somatic inactivation of p53 (TP53) mainly occurs as missense mutations that lead to the acquisition of neomorphic mutant protein forms. p53 mutants have been postulated to exert gain-of-function (GOF) effects, including promotion of metastasis and drug tolerance, which generally contribute to the acquisition of the lethal phenotype. Here, by integrating a p53 R270H -dependent transcriptomic analysis with chromatin accessibility (ATAC-seq) profiling, we shed light on the molecular basis of a p53 mutant-dependent drug-tolerant phenotype in pancreatic cancer. p53 R270H finely tunes chromatin accessibility in specific genomic loci, orchestrating a transcriptional programme that participates in phenotypic evolution of the cancer. We specifically focused on the p53 R270H -dependent regulation of the tyrosine kinase receptor macrophage-stimulating protein receptor (MST1r). MST1r deregulation substantially impinged on drug response in the experimental model, recapitulating the p53 R270H -dependent phenotype, and strongly correlated with p53 mutant and aggressive phenotype in pancreatic cancer patients. As cellular plasticity in the final stages of the evolution of pancreatic cancer seems to predominantly originate from epigenetic mechanisms, we propose that mutant p53 participates in the acquisition of a lethal phenotype by fine-tuning the chromatin landscape.

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Section: Introductionmentioning

confidence: 99%

“…These hot spot mutations either decrease p53 thermodynamic stability or affect DNA-binding activity depending on their location (Joerger and Fersht, 2007). Mutations can impact on the functionality of p53 either leading to a loss of function (LOF) phenotype, a dominant negative (DN) effect on the remaining wild-type p53, or even a gain of function (GOF) activity (Bargonetti and Prives, 2019; Pilley et al, 2021; Sabapathy and Lane, 2018). Aside of the instability of the mutants, wild-type p53 aggregates can form amyloid-like homo and hetero aggregates with mutant p53 (Joerger and Fersht, 2016) with direct impact on p53 activity (de Oliveira et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

The guardian of the genome meets a viral master gene regulator at a biomolecular condensate

Borkosky

Fassolari

Campos-León

et al. 2022

Preprint

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As guardian of the genome, p53 exerts its tumor suppressor activity by modulating the expression of several hundreds of genes and by interacting with a large number of proteins. However, p53 can also repress viral replication and it is targeted by a variety of viral proteins to allow viral replication to proceed. p53 can repress human papillomavirus replication by binding to the viral E2 master gene regulator. Here we show how full-length p53 can spontaneously form phase separated liquid-like droplets that evolve to amyloid-like aggregates in a time-dependent manner, highlighting the fact that homotypic condensation is on the path to aggregation as observed in several protein aggregopathies. The DNA binding domain of HPV E2 (E2C) triggers heterotypic liquid-liquid phase separation with p53 with a precise 1 p53 : 2 E2C stoichiometry at the onset for demixing, yielding large regular spherical droplets that increase in size with E2C concentration. Moreover, E2C is able to slowly reshape time-evolved p53 aggregates into regular heterotypic liquid droplets. Using in situ sub-cellular fractionation, we show that E2 and wild-type p53 co-localize to the nucleus with a grainy pattern, and E2 can re-localize p53 into chromatin associated foci, a function independent of the DNA binding capacity of p53. A small DNA duplex containing the specific binding site for p53 deforms and dissolves both homotypic and heterotypic condensates at a 1 p53 : 1 DNA stoichiometry, whereas a ~1000 base pair DNA fragment instead reshaped the condensates into distinct amorphous condensates containing p53, E2C and DNA, reminiscent of what we observe bound to chromatin. We conclude that p53 is a scaffold for liquid-liquid phase separation in line with its structural and functional features, in particular as a hub that binds multiple cellular protein partners as well as nucleic acids. Moreover, the capacity of E2C to rescue p53 from the amyloid aggregation route impacts on p53-rescuing drugs cancers where p53 mutation leads to loss of function.

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Mutant p53 in cell-cell interactions

Cited by 30 publications

References 162 publications

Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

Levels of p53 expression determine the competitive ability of embryonic stem cells during the onset of differentiation

p53 mutations define the chromatin landscape to confer drug tolerance in pancreatic cancer

The guardian of the genome meets a viral master gene regulator at a biomolecular condensate

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