p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

Fischer, Nicholas W.; Prodeus, Aaron; Malkin, David; Gariépy, Jean

doi:10.1080/15384101.2016.1241917

Cited by 61 publications

(57 citation statements)

References 43 publications

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“…Central to the control of the cell cycle is p53, a tumor suppressor gene that functions in response to DNA damage and can lead to senescence and/or apoptosis. [61][62][63] Once p53 becomes activated by phosphorylation, [64][65][66][67] it upregulates its own transcription, creating a positive feedback loop, as well as another central checkpoint gene p21 (CDKN1A) which acts to inhibit various Cdks, leading to cell cycle arrest. [68][69][70][71][72][73] In parallel, p53 can also activate Bax in the apoptosis pathway promoting programmed cell death.…”

Section: Ehmt2 In Cell Cycle Regulationmentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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Epigenetic regulators play a crucial role in neurodevelopment. One such epigenetic complex, Ehmt1/2 (G9a/GLP), is essential for repressing gene transcription by methylating H3K9 in a highly tissue-and temporal-specific manner. Recently, data has emerged suggesting that this complex plays additional roles in regulating the activity of numerous other non-histone proteins. While much is known about the downstream effects of Ehmt1/2 function, evidence is only beginning to come to light suggesting the control of Ehmt1/2 function may be, at least in part, due to context-dependent binding partners. Here we review emerging roles for the Ehmt1/2 complex suggesting that it may play a much larger role than previously recognized, and discuss binding partners that we and others have recently characterized which act to coordinate its activity during early neurodevelopment.

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Section: Ehmt2 In Cell Cycle Regulationmentioning

confidence: 99%

The expanding role of the Ehmt2/G9a complex in neurodevelopment

2017

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“…It is a well-documented fact that amyloidogenic oligomers of several proteins including p53 are toxic and lead to reduced cell viability (62,63). We Figure 5b).…”

Section: Cytotoxicity Mediated By the [R273x]p53 Oligomersmentioning

confidence: 85%

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

Garg

Hazra

Sannigrahi

et al. 2019

Preprint

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Mutations in p53 protein, especially in the DNA binding domain is one of the major hallmarks of cancer. The R273 position is a DNA contact position and has several oncogenic variants. Surprisingly, cancer patients carrying different mutant-variants of R273 in p53 have different survival rates indicating that the DNA contact inhibition may not be the sole reason for reduced survival with R273 variants.Here, we probed the structural properties of three major oncogenic variants of the R273: ([R273L],[R273H], and [R273C])p53. Using a series of biophysical, biochemical and theoretical simulation studies, we observe that these oncogenic variants of the p53 not only suffer a loss in DNA binding, but also show distinct structural stabilty, aggregation and toxicity profiles. [R273C]p53 shows maximum amyloidogenicity while [R273L]p53 shows maximum aggregation. Further probe in the aggregation mechanism show that [R273C]p53 aggregation is disulphide mediated whereas hydrophobic interactions dominate self-assembly in [R273L]p53. MD simulation studies clearly show that α-helical intermediates are observed in [R273C]p53 whereas β-sheets are observed for [R273L]p53. Our study indicates that each of the R273 variant has its own distinct property of stability and self-assembly, the molecular basis of which, may lead to different types of cancer pathogenesis in vivo. These studies will aid the design of therapeutic strategies for cancer using residue specific or process specific protein aggregation as target.Statement of significance. The present work stems from an interesting observation that genetic mutations that results in switching of one amino acid to different variants at the same codon show different cancer cell progression. We are trying to understand the molecular reason behind the different gain-offunction opted by these variants. With the help of biophysical and biochemical experiments, and computational studies we have observed that the different thermal stability, unique mechanism of unfolding and self-assembly might be one of the crucial parameters for their different oncogenic effect. These studies thus call for the need of developing therapeutic strategies that consider the resultant mutantvariant as a target rather than mutation position. This is an important lead towards the understanding of cancer.cate that specific therapeutic strategies that precisely target the additional effect of the mutation apart from compromised DNA binding is also required for cancer management and cure.

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“…In tetramer conformation p53 exhibits the highest affinity to its DNA-binding elements and efficiently triggers apoptotic transcriptional program (Chène, 2001). Thus, in resting cells the most abundant oligomeric species are p53 dimers that neither promotes cell death nor cell growth, but shift toward tetrameric forms is expected under cellular stress (Fischer et al, 2016). By promoting formation of monomeric or tetrameric structures, multiple p53-binding partners can modify p53 oligomerization and affect cellular response to stress (van Dieck et al, 2009).…”

Section: Role Of P53 In Neuronal Biologymentioning

confidence: 99%

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

Jembrek

Slade

Hof

et al. 2018

Progress in Neurobiology

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Alzheimer's disease (AD), the most common progressive neurodegenerative disorder, is characterized by severe cognitive decline and personality changes as a result of synaptic and neuronal loss. The defining clinicopathological hallmarks of the disease are deposits of amyloid precursor protein (APP)-derived amyloid-β peptides (Aβ) in the brain parenchyma, and intracellular aggregates of truncated and hyperphosphorylated tau protein in neurofibrillary tangles (NFT). At the cellular and molecular levels, many intertwined pathological mechanisms that relate Aβ and tau pathology with a transcription factor p53 have been revealed. p53 is activated in response to various stressors that threaten genomic stability. Depending on damage severity, it promotes neuronal death or survival, predominantly via transcription-dependent mechanisms that affect expression of apoptosis-related target genes. Levels of p53 are enhanced in the AD brain and maintain sustained tau hyperphosphorylation, whereas intracellular Aβ directly contributes to p53 pool and promotes downstream p53 effects. The review summarizes the role of p53 in neuronal function, discusses the interactions of p53, tau, and Aβ in the normal brain and during the progression of AD pathology, and considers the impact of the most prominent hereditary risk factors of AD on p53/tau/Aβ interactions. A better understanding of this intricate interplay would provide deeper insight into AD pathology and might offer some novel therapeutic targets for the improvement of treatment options. In this regard, drugs and natural compounds targeting the p53 pathway are of growing interest in neuroprotection as they may represent promising therapeutic approaches in the prevention of oxidative stress-dependent pathological processes underlying AD.

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p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis

Cited by 61 publications

References 43 publications

The expanding role of the Ehmt2/G9a complex in neurodevelopment

The expanding role of the Ehmt2/G9a complex in neurodevelopment

Variable Mutations at the p53-R273 Oncogenic Hotspot Position Leads to Altered Properties

The interactions of p53 with tau and Aß as potential therapeutic targets for Alzheimer’s disease

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