Dynamics of P53 in response to DNA damage: Mathematical modeling and perspective

Sun, Tingzhe; Cui, Jun

doi:10.1016/j.pbiomolbio.2015.08.017

Cited by 26 publications

(19 citation statements)

References 108 publications

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“…If the ensuing chronic stress is sufficiently strong and is sustained (>12 hours), cells undergo apoptosis [56]. By analogy, the “guardian of the genome”—p53—elicits cell death if aberrations at the DNA level are not dealt with in a timely manner [57, 58]. The UPR-mediated pro-apoptotic mechanism may serve to preserve resources and prevent deleterious consequences of persistent stress.…”

Section: Introductionmentioning

confidence: 99%

Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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Cells respond to internal and external cellular stressors by activating stress response pathways that re-establish homeostasis. If homeostasis is not achieved in a timely manner, stress pathways trigger programmed cell death (apoptosis) to preserve organism integrity. A highly-conserved stress pathway is the unfolded protein response (UPR), which senses excessive amounts of unfolded proteins in the ER. While a physiologically beneficial pathway, the UPR requires tight regulation to provide a beneficial outcome and avoid deleterious consequences. Recent work has demonstrated that a conserved and highly selective RNA degradation pathway—Nonsense-Mediated RNA Decay (NMD)—serves as a major regulator of the UPR pathway. NMD degrades mRNAs encoding UPR components to prevent UPR activation in response to innocuous ER stress. In response to strong ER stress, NMD is inhibited by the UPR to allow for a full-magnitude UPR response. Recent studies have indicated that NMD also has other stress-related functions, including promoting the timely termination of the UPR to avoid apoptosis; NMD also regulates responses to non-ER stressors, including hypoxia, amino-acid deprivation, and pathogen infection. NMD regulates stress responses in species across the phylogenetic scale, suggesting it has conserved roles in shaping stress responses. Stress pathways are frequently constitutively activated or dysregulated in human disease, raising the possibility that “NMD therapy” may provide clinical benefit by downmodulating stress responses.

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Section: Introductionmentioning

confidence: 99%

Stress and the nonsense-mediated RNA decay pathway

Goetz

Wilkinson

2017

Cell. Mol. Life Sci.

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“…Advances and perspectives regarding the dynamics and mathematical models of p53 signaling in response to different types of DNA damage, together with insight into the biological functions of such dynamics, have been extensively reviewed [32,37] and will not be considered further.…”

Section: Biological Outputs Orchestrated By Wild-type P53mentioning

confidence: 99%

Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

Mirzayans

Andrais

Kumar

et al. 2017

IJMS

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Our genomes are subject to potentially deleterious alterations resulting from endogenous sources (e.g., cellular metabolism, routine errors in DNA replication and recombination), exogenous sources (e.g., radiation, chemical agents), and medical diagnostic and treatment applications. Genome integrity and cellular homeostasis are maintained through an intricate network of pathways that serve to recognize the DNA damage, activate cell cycle checkpoints and facilitate DNA repair, or eliminate highly injured cells from the proliferating population. The wild-type p53 tumor suppressor and its downstream effector p21WAF1 (p21) are key regulators of these responses. Although extensively studied for its ability to control cell cycle progression, p21 has emerged as a multifunctional protein capable of downregulating p53, suppressing apoptosis, and orchestrating prolonged growth arrest through stress-induced premature senescence. Studies with solid tumors and solid tumor-derived cell lines have revealed that such growth-arrested cancer cells remain viable, secrete growth-promoting factors, and can give rise to progeny with stem-cell-like properties. This article provides an overview of the mechanisms by which p53 signaling suppresses apoptosis following genotoxic stress, facilitating repair of genomic injury under physiological conditions but having the potential to promote tumor regrowth in response to cancer chemotherapy.

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“…It seems that under normal conditions, fractional ATM activities are attenuated by DNA-PK to avoid fast commitment to death and allow faithful DNA repair. The information flows are encoded uniformly possibly potentiating pulse counting in theoretical p53 models [17]. However, DNA-PK inhibitor treatment amplifies and shift the information flows towards the first pulses.…”

Section: Discussionmentioning

confidence: 99%

“…Previous mathematical models have not explored the prolonged activation of the first p53 pulse under DNA-PK inhibition [11, 12, 15, 17, 18]. Therefore, we constructed a simplified mathematical model which incorporated novel interplay among PIKK family members as well as their coordinated activation of downstream effector p53 module.…”

Section: Introductionmentioning

confidence: 99%

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

Sun

Shen

2017

Oncotarget

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During DNA double strand breaks (DSBs) repair, coordinated activation of phosphatidylinositol 3-kinase (PI3K)-like kinases can activate p53 signaling pathway. Recent findings have identified novel interplays among these kinases demonstrating amplified first p53 pulses under DNA-PK inhibition. However, no theoretical model has been developed to characterize such dynamics. In current work, we modeled the prolonged p53 pulses with DNA-PK inhibitor. We could identify a dose-dependent increase in the first pulse amplitude and width. Meanwhile, weakened DNA-PK mediated ATM inhibition was insufficient to reproduce such dynamic behavior. Moreover, the information flow was shifted predominantly to the first pulse under DNA-PK inhibition. Furthermore, the amplified p53 responses were relatively robust. Taken together, our model can faithfully replicate amplified p53 responses under DNA-PK inhibition and provide insights into cell fate decision by manipulating p53 dynamics.

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Dynamics of P53 in response to DNA damage: Mathematical modeling and perspective

Cited by 26 publications

References 108 publications

Stress and the nonsense-mediated RNA decay pathway

Stress and the nonsense-mediated RNA decay pathway

Significance of Wild-Type p53 Signaling in Suppressing Apoptosis in Response to Chemical Genotoxic Agents: Impact on Chemotherapy Outcome

Modeling amplified p53 responses under DNA-PK inhibition in DNA damage response

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