Genome Stability Requires p53

Eischen, Christine M.

doi:10.1101/cshperspect.a026096

Cited by 110 publications

(81 citation statements)

References 134 publications

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“…In an alternative but non-mutually exclusive explanation, p53 can restrict chromosomal instability through its ability to cull cells at risk of aberrant mitoses, particularly following centrosome amplification and/or telomere dysfunction (Dewhurst et al, 2014; Eischen, 2016; Lanni and Jacks, 1998). Extra centrosomes lead to Hippo pathway up-regulation that, in turn, activates p53 by inhibiting MDM2 (Aylon et al, 2006; Ganem et al., 2014).…”

Section: Revisiting the Guardian Of The Genomementioning

confidence: 99%

Putting p53 in Context

Kastenhuber

Lowe

2017

Cell

1,425

1,285

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TP53 is the most frequently mutated gene in human cancer. Functionally, p53 is activated by a host of stress stimuli and, in turn, governs an exquisitely complex anti-proliferative transcriptional program that touches upon a bewildering array of biological responses. Despite the many unveiled facets of the p53 network, a clear appreciation of how and in what contexts p53 exerts its diverse effects remains unclear. How can we interpret p53’s disparate activities and the consequences of its dysfunction to understand how cell type, mutation profile, and epigenetic cell state dictate outcomes, and how might we restore its tumor suppressive activities in cancer?

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Section: Revisiting the Guardian Of The Genomementioning

confidence: 99%

Putting p53 in Context

Kastenhuber

Lowe

2017

Cell

1,425

1,285

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“…2D and E). Multipolar spindle formation has been reported to occur frequently in p53-deficient cancer cells, and tripolar cell division has also often been reported in malignant cancer cells (21)(22)(23)(24). Interestingly, the frequency of tripolar cell divisions was significantly increased by p53 silencing (Fig.…”

Section: Analysis Of Multipolar Cell Division Cell Death and Cell Fmentioning

confidence: 75%

Empirical single-cell tracking and cell-fate simulation reveal dual roles of p53 in tumor suppression

Rancourt¹,

Sato

Satoh

2018

Preprint

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p53 regulates a broad range of processes in cells exposed to various stresses. Although, in unstressed cells, p53 is maintained at low levels, it is unclear if these low levels of p53 have any functional roles. Thus, we investigated the roles of basal levels of p53 using a single-cell lineage tracking technique. We compared the spatiotemporal responses of p53-proficient cancer cells with cells in which p53 gene expression had been silenced. We found that the p53-proficient cell population included a subpopulation of fast-growing cells with a shorter cell-doubling time than other slowgrowing cells. p53 silencing reduced the cell-doubling time of the slow-growing cells, thus converting them to faster growing cells. In contrast, the growth rate of the fast-growing cells was unaffected by basal levels of p53, suggesting that growth of slow-growing but not fast-growing cells were regulated by p53 levels. In addition, silencing p53 increased the incidences of multipolar cell division and cell death among the slow-growing cells. These results suggest that basal levels of p53 act to maintain a balance between the fast-and slow-growing cell subpopulations and to suppress the occurrence of abnormal cellular events. We therefore propose that basal levels of p53 help to control cell population homeostasis by regulating the growth and maintaining the integrity of slow-growing cells.Rancourt et al. 3

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“…According to the theory of tumorigenesis, the DDR triggers the senescence inflammation response (SIR) and SASP activation, and genomic instability results in the activation of oncogenes and the dysfunction of tumor suppressor genes (Pribluda et al, ). SIR‐induced p53 gene family activation drives the DNA repair system to recover from genomic instability and maintain tissue homeostasis; however, the dysfunction of p53 family genes (or tumor suppressor genes) that results from genomic instability can promote tumorigenesis (Eischen, 2016). Treatment with nonsteroidal anti‐inflammatory drugs as tumor preventive agents restrains tumorigenesis by blocking inflammation (Gurpinar, Grizzle, & Piazza, ).…”

Section: Discussionmentioning

confidence: 99%

Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging‐associated tumorigenesis induced by ultraviolet B

Hsu

Tsai

et al. 2019

Aging Cell

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Aging, cancer, and longevity have been linked to intracellular Ca2+ signaling and nociceptive transient receptor potential (TRP) channels. We found that TRP canonical 7 (TRPC7) is a nociceptive mechanoreceptor and that TRPC7 channels specifically mediate the initiation of ultraviolet B (UVB)‐induced skin aging and tumor development due to p53 gene family mutations. Within 30 min after UVB irradiation, TRPC7 mediated UVB‐induced Ca2+ influx and the subsequent production of reactive oxygen species in skin cells. Notably, this function was unique to TRPC7 and was not observed for other TRP channels. In TRPC7 knockout mice, we did not observe the significant UVB‐associated pathology seen in wild‐type mice, including epidermal thickening, abnormal keratinocyte differentiation, and DNA damage response activation. TRPC7 knockout mice also had significantly fewer UVB‐induced cancerous tumors than did wild‐type mice, and UVB‐induced p53 gene family mutations were prevented in TRPC7 knockout mice. These results indicate that TRPC7 activity is pivotal in the initiation of UVB‐induced skin aging and tumorigenesis and that the reduction in TRPC7 activity suppresses the UVB‐induced aging process and tumor development. Our findings support that TRPC7 is a potential tumor initiator gene and that it causes cell aging and genomic instability, followed by a change in the activity of proto‐oncogenes and tumor suppressor genes to promote tumorigenesis.

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Genome Stability Requires p53

Cited by 110 publications

References 134 publications

Putting p53 in Context

Putting p53 in Context

Empirical single-cell tracking and cell-fate simulation reveal dual roles of p53 in tumor suppression

Nociceptive transient receptor potential canonical 7 (TRPC7) mediates aging‐associated tumorigenesis induced by ultraviolet B

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