Mechanical cell competition kills cells via induction of lethal p53 levels

Wagstaff, Laura; Goschorska, Maja; Kozyrska, Kasia; Duclos, Guillaume; Kuciński, Iwo; Chessel, Anatole; Hampton-O'Neil, Lea A; Bradshaw, Charles R.; Allen, George E.; Rawlins, Emma L.; Silberzan, Pascal; Carazo-Salas, Rafael E.; Piddini, Eugenia

doi:10.1038/ncomms11373

Cited by 179 publications

(268 citation statements)

References 70 publications

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“…This model may apply to several mutations that promote growth/proliferation and inhibit apoptosis (e.g., Hippo pathway, Ras, EGF). A similar process was recently involved in the elimination of Scribble mutant MDCK cells surrounded by WT cells [67]. The higher levels of p53 in Scribble mutant cells increase their sensitivity to compaction, which is sensed through the activation of p53 by Rho-associated kinase (ROCK) and the stress kinase p38.…”

Section: ([ 5 _ T D $ D I F F ] Figures 1c And[ 1 _ T D $ D I F F ]mentioning

confidence: 72%

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

Merino

Levayer

Moreno

2016

Trends in Cell Biology

123

109

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Section: ([ 5 _ T D $ D I F F ] Figures 1c And[ 1 _ T D $ D I F F ]mentioning

confidence: 72%

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

Merino

Levayer

Moreno

2016

Trends in Cell Biology

123

109

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“…The activation of myosin-II generates pulling-forces exerted at the interface between normal and transformed cells, thereby promoting apical extrusion of the transformed cells (6). Along the same line, recent studies have revealed that physical forces or mechanical tensions can play a crucial role in cell competition between normal and transformed epithelial cells (32,33). Thus, the EPLIN-myosin-II pathway could be another endocytosismediated regulatory mechanism for apical extrusion.…”

Section: Discussionmentioning

confidence: 98%

Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

Saitoh

Maruyama

Yako

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Newly emerging transformed cells are often eliminated from epithelial tissues. Recent studies have revealed that this cancer-preventive process involves the interaction with the surrounding normal epithelial cells; however, the molecular mechanisms underlying this phenomenon remain largely unknown. In this study, using mammalian cell culture and zebrafish embryo systems, we have elucidated the functional involvement of endocytosis in the elimination of RasV12-transformed cells. First, we show that Rab5, a crucial regulator of endocytosis, is accumulated in RasV12-transformed cells that are surrounded by normal epithelial cells, which is accompanied by upregulation of clathrin-dependent endocytosis. Addition of chlorpromazine or coexpression of a dominant-negative mutant of Rab5 suppresses apical extrusion of RasV12 cells from the epithelium. We also show in zebrafish embryos that Rab5 plays an important role in the elimination of transformed cells from the enveloping layer epithelium. In addition, Rab5-mediated endocytosis of E-cadherin is enhanced at the boundary between normal and RasV12 cells. Rab5 functions upstream of epithelial protein lost in neoplasm (EPLIN), which plays a positive role in apical extrusion of RasV12 cells by regulating protein kinase A. Furthermore, we have revealed that epithelial defense against cancer (EDAC) from normal epithelial cells substantially impacts on Rab5 accumulation in the neighboring transformed cells. This report demonstrates that Rab5-mediated endocytosis is a crucial regulator for the competitive interaction between normal and transformed epithelial cells in mammals.cell competition | endocytosis | apical extrusion | Rab5 | RasV12

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“…They also used Mdm2 +/− hematopoietic stem and progenitor cells to genetically mimic mild p53 activation induced by a low level of irradiation and found that these cells were outcompeted by the wild-type donor in the chimeric hematopoietic system (29). More recently, it was shown that p53 may instruct an out-competition phenotype of the scrib KD cells in response to cell crowding (30). However, it remains elusive whether cell competition represents a general mechanism in p53-mediated cellular responses or occurs only under specific circumstances.…”

Section: Mdm4mentioning

confidence: 99%

p53 pathway is involved in cell competition during mouse embryogenesis

Zhang

Xie

Zhou

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The function of tumor suppressor p53 has been under intense investigation. Acute stresses such as DNA damage are able to trigger a high level of p53 activity, leading to cell cycle arrest or apoptosis. In contrast, the cellular response of mild p53 activity induced by low-level stress in vivo remains largely unexplored. Murine double minute (MDM)2 and MDM4 are two major negative regulators of p53. Here, we used the strategy of haploinsufficiency of Mdm2 and Mdm4 to induce mild p53 activation in vivo and found that Mdm2+/−Mdm4+/− double-heterozygous mice exhibited normal embryogenesis. However, closer examination demonstrated that the Mdm2+/−Mdm4+/− cells exhibited a growth disadvantage and were outcompeted during development in genetic mosaic embryos that contained wild-type cells. Further study indicated the out-competition phenotype was dependent on the levels of p53. These observations revealed that cells with mild p53 activation were less fit and exhibited altered fates in a heterotypic environment, resembling the cell competition phenomenon first uncovered in Drosophila. By marking unfit cells for elimination, p53 may exert its physiological role to ensure organ and animal fitness.

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Mechanical cell competition kills cells via induction of lethal p53 levels

Cited by 179 publications

References 70 publications

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

p53 pathway is involved in cell competition during mouse embryogenesis

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