Cell competition: Winning out by losing notch

Alcolea, Maria P.; Jones, Philip H.

doi:10.4161/15384101.2014.988027

Cited by 36 publications

(31 citation statements)

References 72 publications

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“…The analysis of Krt10 induction in monolayer NIKS expressing E6 mutants confirmed that the ability of E6 to degrade p53 is indeed necessary to prevent commitment to differentiation, whereas the PDZ‐binding defective E6 mutant retains the ability to significantly modulate keratinocyte differentiation ( p = 0.0162, Student's t ‐test) (Figure F). Taken together, these results support previous observations and allow us to conclude that p53 and Notch1 are crucial regulators of keratinocyte cell fate .…”

Section: Resultssupporting

confidence: 91%

“…Taken together, these results support previous observations [37,41] and allow us to conclude that p53 and Notch1 are crucial regulators of keratinocyte cell fate [12,13,21].…”

Section: Hpv-16 E6 Requires Interaction With P53 But Not Pdz Proteinssupporting

confidence: 91%

“…Such a potent fate-determining effect has been hypothesized to occur when asymmetric cell divisions lead to the inheritance of a stronger Notch signal by one of the daughter cells, thereby counteracting proliferative signals and promoting differentiation [65,66]. This scenario is also supported by recent studies in mice, where the accumulation of inactivating mutations in Tp53 and Notch genes confers a so-called 'super-competitor' phenotype, skewing keratinocyte cell fate towards proliferation rather than differentiation [13,21]. This allows the persistence and clonal expansion of mutant cell populations, and similar mechanisms of clonal persistence have been recently described in sun-exposed human skin [12].…”

Section: Discussionmentioning

confidence: 92%

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Modulation of basal cell fate during productive and transforming HPV-16 infection is mediated by progressive E6-driven depletion of Notch

et al. 2017

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In stratified epithelia such as the epidermis, homeostasis is maintained by the proliferation of cells in the lower epithelial layers and the concomitant loss of differentiated cells from the epithelial surface. These differentiating keratinocytes progressively stratify and form a self‐regenerating multi‐layered barrier that protects the underlying dermis. In such tissue, the continual loss and replacement of differentiated cells also limits the accumulation of oncogenic mutations within the tissue. Inactivating mutations in key driver genes, such as TP53 and NOTCH1, reduce the proportion of differentiating cells allowing for the long‐term persistence of expanding mutant clones in the tissue. Here we show that through the expression of E6, HPV‐16 prevents the early fate commitment of human keratinocytes towards differentiation and confers a strong growth advantage to human keratinocytes. When E6 is expressed either alone or with E7, it promotes keratinocyte proliferation at high cell densities, through the combined inactivation of p53 and Notch1. In organotypic raft culture, the activity of E6 is restricted to the basal layer of the epithelium and is enhanced during the progression from productive to abortive or transforming HPV‐16 infection. Consistent with this, the expression of p53 and cleaved Notch1 becomes progressively more disrupted, and is associated with increased basal cell density and reduced commitment to differentiation. The expression of cleaved Notch1 is similarly disrupted also in HPV‐16‐positive cervical lesions, depending on neoplastic grade. When taken together, these data depict an important role of high‐risk E6 in promoting the persistence of infected keratinocytes in the basal and parabasal layers through the inactivation of gene products that are commonly mutated in non‐HPV‐associated neoplastic squamous epithelia. © 2017 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Resultssupporting

confidence: 91%

“…Taken together, these results support previous observations [37,41] and allow us to conclude that p53 and Notch1 are crucial regulators of keratinocyte cell fate [12,13,21].…”

Section: Hpv-16 E6 Requires Interaction With P53 But Not Pdz Proteinssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 92%

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Modulation of basal cell fate during productive and transforming HPV-16 infection is mediated by progressive E6-driven depletion of Notch

et al. 2017

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“…Even in the absence of supercompetitors, D. melanogaster has evolved effective mechanisms to prolong lifespan by eliminating 'unfit' but otherwise viable populations dur ing development and ageing 47 . Studies such as these have inspired researchers to investigate cell competition and other similar cellular interactions in mammalian sys tems as well 48 . Despite being functionally different, these and other similar studies have also provided important insights into some of the mechanisms that may be at play among interacting cancer cells.…”

Section: Clonal Cooperation In Drosophila Melanogastermentioning

confidence: 99%

Tumorigenesis: it takes a village

2015

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Although it is widely accepted that most cancers exhibit some degree of intratumour heterogeneity, we are far from understanding the dynamics that operate among subpopulations within tumours. There is growing evidence that cancer cells behave as communities, and increasing attention is now being directed towards the cooperative behaviour of subclones that can influence disease progression. As expected, these interactions can add a greater layer of complexity to therapeutic interventions in heterogeneous tumours, often leading to a poor prognosis. In this Review, we highlight studies that demonstrate such interactions in cancer and postulate ways to overcome them with better-designed therapeutic strategies.

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“…15 Deregulated Notch signaling has been observed in a variety of human cancers including prostate cancer. [16][17][18][19] For example, Jagged-1 expression is associated with prostate cancer metastasis and recurrence. 20 Similarly, another study showed that elevated Jagged-1 and Notch-1 expression was found in high grade and metastatic prostate cancers.…”

Section: Introductionmentioning

confidence: 99%