The Yes-associated protein controls the cell density regulation of Hedgehog signaling

Tariki, Melanie; Dhanyamraju, Pavan Kumar; Fendrich, Volker; Borggrefe, Tilman; Feldmann, Georg; Lauth, Matthias

doi:10.1038/oncsis.2014.27

Cited by 46 publications

(45 citation statements)

References 32 publications

(44 reference statements)

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“…Contact inhibition is a well‐recognized cell biological process whereby cell proliferation ceases when cultured cells come into contact as a confluent monolayer (Abercrombie, 1967) and is mediated through the Hippo signalling pathway involving the target transcription factors YAP/TAZ (Tariki et al ., 2014) which are responsive to mechanical forces (Aragona et al ., 2013). Sparse cultures of RPE cells in vitro proliferate extensively and adopt an EMT‐like spindle shape morphology (Newsome, 1983; Chen et al ., 2012), but under appropriate conditions differentiate into a typical hexagonal nonproliferating RPE monolayer (Newsome, 1983).…”

Section: Discussionmentioning

confidence: 99%

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

et al. 2016

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SummaryRetinal pigment epithelial (RPE) cells are central to retinal health and homoeostasis. Dysfunction or death of RPE cells underlies many age‐related retinal degenerative disorders particularly age‐related macular degeneration. During aging RPE cells decline in number, suggesting an age‐dependent cell loss. RPE cells are considered to be postmitotic, and how they repair damage during aging remains poorly defined. We show that RPE cells increase in size and become multinucleate during aging in C57BL/6J mice. Multinucleation appeared not to be due to cell fusion, but to incomplete cell division, that is failure of cytokinesis. Interestingly, the phagocytic activity of multinucleate RPE cells was not different from that of mononuclear RPE cells. Furthermore, exposure of RPE cells in vitro to photoreceptor outer segment (POS), particularly oxidized POS, dose‐dependently promoted multinucleation and suppressed cell proliferation. Both failure of cytokinesis and suppression of proliferation required contact with POS. Exposure to POS also induced reactive oxygen species and DNA oxidation in RPE cells. We propose that RPE cells have the potential to proliferate in vivo and to repair defects in the monolayer. We further propose that the conventionally accepted ‘postmitotic’ status of RPE cells is due to a modified form of contact inhibition mediated by POS and that RPE cells are released from this state when contact with POS is lost. This is seen in long‐standing rhegmatogenous retinal detachment as overtly proliferating RPE cells (proliferative vitreoretinopathy) and more subtly as multinucleation during normal aging. Age‐related oxidative stress may promote failure of cytokinesis and multinucleation in RPE cells.

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Section: Discussionmentioning

confidence: 99%

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

et al. 2016

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Section: The Many Nodes That Connect To Hippo Signalingmentioning

confidence: 99%

“…On the other hand, activation of SHH inversely correlates with the expression of nuclear YAP in pancreatic adenocarcinoma (99). Gli2 , a major transcriptional mediator of Hedgehog signaling, has been identified as a transcriptional target of YAP/TEAD in neural precursors (49), while YAP can bind to and inhibit GLI transcription factors in fibroblasts resulting in decreased expression of Hedgehog pathway targets (99). Importantly, Hippo upstream kinases as well as YAP/TAZ are involved ciliogenesis of the primary cilium (100, 101), an organelle of the plasma membrane that is an important determinant of Hedgehog signaling (and other signaling pathways).…”

Section: The Many Nodes That Connect To Hippo Signalingmentioning

confidence: 99%

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Ehmer

Sage

2016

Molecular Cancer Research

122

101

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The control of cell division is essential for normal development and the maintenance of cellular homeostasis. Abnormal cell proliferation is associated with multiple pathological states, including cancer. While the Hippo/YAP signaling pathway was initially thought to control organ size and growth, increasing evidence indicates that this pathway also plays a major role in the control of proliferation independent of organ size control. In particular, accumulating evidence indicates that the Hippo/YAP signaling pathway functionally interacts with multiple other cellular pathways and serves as a central node in the regulation of cell division, especially in cancer cells. Here recent observations are highlighted that connect Hippo/YAP signaling to transcription, the basic cell cycle machinery, and the control of cell division. Furthermore, the oncogenic and tumor suppressive attributes of YAP/TAZ are reviewed which emphasizes the relevance of the Hippo pathway in cancer.

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“…Progress is likely to be expedited by earlier work, which demonstrated mechanisms that control RDC accumulation in human and murine NAFLD [8, 9]. Some of these signaling pathways (e.g., Hedgehog) have been linked to YAP activation in other tissues and certain cancers [10–12]. …”

Section: Introductionmentioning

confidence: 99%

Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease

Machado¹,

Michelotti²,

Pereira³

et al. 2015

Journal of Hepatology

102

100

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Background & Aims Mechanisms that regulate regeneration of injured livers are complex. YAP, a stem-cell associated factor, controls liver growth in healthy adult mice. Increasing nuclear localization of YAP triggers accumulation of reactive-appearing ductular cells (YAP+RDC) with liver progenitor capabilities. The significance of YAP activation, and mechanisms involved, are unknown in diseased livers. We evaluated the hypothesis that YAP is more activated in injured livers that are scarring than in those that are regenerating effectively. Methods Immunohistochemistry and qRT-PCR analysis were used to localize and quantify changes in YAP and RDC in 52 patients with nonalcoholic fatty liver disease (NAFLD) and two mouse models of diet-induced nonalcoholic steatohepatitis (NASH). Results were correlated with liver disease severity, metabolic risk factors, and factors proven to control NAFLD progression. Results YAP increased in NAFLD where it mainly localized in nuclei of RDC that expressed progenitor markers. Accumulation of YAP+RDC paralleled the severity of hepatocyte injury and accumulation of Sonic hedgehog (Shh), but not steatosis or metabolic risk factors. YAP+RDC expressed osteopontin, a Shh-regulated fibrogenic factor. Myofibroblast accumulation, fibrosis, and numbers of YAP+RDC strongly correlated. In murine NASH models, atrophic fibrotic livers contained significantly more YAP+RDC than livers with less severe NASH. Conclusion YAP+RDC promote scarring, rather than effective regeneration, during NASH.

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The Yes-associated protein controls the cell density regulation of Hedgehog signaling

Cited by 46 publications

References 32 publications

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

Retinal pigment epithelial cell multinucleation in the aging eye - a mechanism to repair damage and maintain homoeostasis

Control of Proliferation and Cancer Growth by the Hippo Signaling Pathway

Accumulation of duct cells with activated YAP parallels fibrosis progression in non-alcoholic fatty liver disease

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