Dynamics of p53: A Master Decider of Cell Fate

Luo, Qingyin; Beaver, Jill M.; Liu, Yuan; Zhang, Zunzhen

doi:10.3390/genes8020066

Cited by 71 publications

(65 citation statements)

References 66 publications

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“…Collectively, transcription factors can complement each other through the diversity in their responses (31) as well as averaging biochemical stochasticity. Paralleling discoveries in neuroscience, we expect that such multi-dimensional internal representations are widespread within cellular biology and their failures in encoding information, by causing dysfunctional decisionmaking, can instigate deleterious behaviors and disease (32).…”

Section: Resultsmentioning

confidence: 98%

Distributed and dynamic intracellular organization of extracellular information

Granados

Pietsch²,

Cepeda-Humerez

et al. 2017

Preprint

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Although cells respond specifically to environments, how environmental identity is encoded intracellularly is not understood. Here we study this organization of information in budding yeast by estimating the mutual information between environmental transitions and the dynamics of nuclear translocation for ten transcription factors. Our method of estimation is general, scalable, and based on decoding from single cells. The dynamics of the transcription factors are necessary to encode the highest amounts of extracellular information, and we show that information is transduced through two channels: generalists (Msn2/4, Tod6/Dot6, Maf1, and Sfp1) can encode the nature of multiple stresses but only if stress is high; specialists (Hog1, Yap1, and Mig1/2) encode one particular stress, but do so more quickly and for a wider range of magnitudes. Each transcription factor reports differently, and it is only their collective response that distinguishes between multiple environmental states. Changes in the dynamics of the localization of transcription factors thus constitute a precise, distributed internal representation of extracellular change, and we predict that such multi-dimensional representations are common in cellular decision-making. Significance StatementTo thrive in diverse environments, cells must represent extracellular change intracellularly despite stochastic biochemistry. Here we introduce a quantitative framework for investigating the organization of information within a cell. Combining single-cell measurements of intracellular dynamics with a new, scalable methodology for estimating mutual information between time-series and a discrete input, we demonstrate that extracellular information is encoded in the dynamics of the nuclear localization of transcription factors and that information is lost with alternative static statistics. Any one transcription factor is usually insufficient, but the collective dynamics of multiple transcription factors can represent complex extracellular change. We therefore show that a cell's internal representation of its environment can be both distributed across diverse proteins and dynamically encoded.

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Section: Resultsmentioning

confidence: 98%

Distributed and dynamic intracellular organization of extracellular information

Granados

Pietsch²,

Cepeda-Humerez

et al. 2017

Preprint

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“…In addition to p53 acetylation, p53 phosphorylation also plays a crucial role in the activation and promotion of apoptosis. The phosphorylation of p53 at Ser46 following severe DNA damage increases the affinity of p53 to the promoters of pro‐apoptotic genes such as p53AIP1 . Naoe Taira et al demonstrated that dual‐specificity tyrosine‐phosphorylation‐regulated kinase 2 (DYRK2) can directly phosphorylate p53 at Ser46 upon exposure to genotoxic stress .…”

Section: Discussionmentioning

confidence: 99%

RNF8 promotes efficient DSB repair by inhibiting the pro‐apoptotic activity of p53 through regulating the function of Tip60

et al. 2020

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Objectives RING finger protein 8 (RNF8) is an E3 ligase that plays an essential role in DSB repair. p53 is a well‐established tumour suppressor and cellular gatekeeper of genome stability. This study aimed at investigating the functional correlations between RNF8 and p53 in DSB damage repair. Materials and methods In this article, wild‐type, knockout and shRNA‐depleted HCT116 and U2OS cells were stressed, and the roles of RNF8 and p53 were examined. RT‐PCR and Western blot were utilized to investigate the expression of related genes in damaged cells. Cell proliferation, apoptosis and neutral cell comet assays were applied to determine the effects of DSB damage on differently treated cells. DR‐GFP, EJ5‐GFP and LacI‐LacO targeting systems, flow cytometry, mass spectrometry, IP, IF, GST pull‐down assay were used to explore the molecular mechanism of RNF8 and p53 in DSB damage repair. Results We found that RNF8 knockdown increased cellular sensitivity to DSB damage and decreased cell proliferation, which was correlated with high expression of the p53 gene. RNF8 improved the efficiency of DSB repair by inhibiting the pro‐apoptotic function of p53. We also found that RNF8 restrains cell apoptosis by inhibiting over‐activation of ATM and subsequently reducing p53 acetylation at K120 through regulating Tip60. Conclusions Taken together, these findings suggested that RNF8 promotes efficient DSB repair by inhibiting the pro‐apoptotic activity of p53 through regulating the function of Tip60.

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“…Cellular damage caused by extrinsic or intrinsic factors is capable of activating cell cycle checkpoints, resulting in arrest of the cell cycle, which allows the cell to repair any damage before continuing (72)(73)(74). The p53 protein is activated by an array of cellular stresses and has a central role in deciding the fate of the cell through inducing arrest or apoptosis (27). We show here that CaMKIV-induced CREB activation during experimental colitis is associated with increased levels of p53, which appears to result in up-regulation of p21 and subsequent cell cycle arrest.…”

Section: Discussionmentioning

confidence: 67%

Calcium/calmodulin–dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation

et al. 2018

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The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide. IBD is known to be multifactorial, but inflammatory signaling within the intestinal epithelium and a subsequent failure of the intestinal epithelial barrier have been shown to play essential roles in disease pathogenesis. CaMKIV is a multifunctional protein kinase associated with inflammation and cell cycle regulation. CaMKIV has been extensively studied in autoimmune diseases, but a role in idiopathic intestinal inflammation has not been described. In this study, active CaMKIV was highly expressed within the intestinal epithelium of humans with ulcerative colitis and wild-type (WT) mice with experimental induced colitis. Clinical disease severity directly correlates with CaMKIV activation, as does expression of proinflammatory cytokines and histologic features of colitis. In WT mice, CaMKIV activation is associated with increases in expression of 2 cell cycle proarrest signals: p53 and p21. Cell cycle arrest inhibits proliferation of the intestinal epithelium and ultimately results in compromised intestinal epithelial barrier integrity, further perpetuating intestinal inflammation during experimental colitis. Using a CaMKIV null mutant mouse, we demonstrate that a loss of CaMKIV protects against murine DSS colitis. Small molecules targeting CaMKIV activation may provide therapeutic benefit for patients with IBD.-Cunningham, K. E., Novak, E. A., Vincent, G., Siow, V. S., Griffith, B. D., Ranganathan, S., Rosengart, M. R., Piganelli, J. D., Mollen, K. P. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation.

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Dynamics of p53: A Master Decider of Cell Fate

Cited by 71 publications

References 66 publications

Distributed and dynamic intracellular organization of extracellular information

Distributed and dynamic intracellular organization of extracellular information

RNF8 promotes efficient DSB repair by inhibiting the pro‐apoptotic activity of p53 through regulating the function of Tip60

Calcium/calmodulin–dependent protein kinase IV (CaMKIV) activation contributes to the pathogenesis of experimental colitis via inhibition of intestinal epithelial cell proliferation

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