Dmp53 Activates the Hippo Pathway to Promote Cell Death in Response to DNA Damage

Colombani, Julien; Polesello, Cédric; Josué, Filipe; Tapon, Nicolas

doi:10.1016/j.cub.2006.05.059

Cited by 57 publications

(56 citation statements)

References 32 publications

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“…These findings corroborate the idea that the Hippo pathway plays an important role in mediating responses to xenobiotic stress. Activation of Hpo kinase occurs through phosphorylation of its kinase domain (on T195), 42 and consistent with this, we found increased levels of phosphorylated Hpo in flies fed with caffeine, suggesting that drug exposure promotes Hpo activation.…”

Section: Discussionsupporting

confidence: 88%

“…41 Although the Hippo signaling pathway is best characterized for controlling tissue size, some work in Drosophila has linked the pathway to genotoxic stress 42 and alcohol-induced stress. 43 These studies, however, did not propose a molecular mechanism that could explain the role of Hippo as a modulator of stress response pathways.…”

Section: Resultsmentioning

confidence: 99%

“…We monitored the phosphorylation status of residue T195 in the kinase domain activation loop, which is required for Hpo activity. 42 We analyzed the levels of phosphorylated Hpo kinase by western blotting, and compared control animals (third instar (L3) larvae of ey4w 1118 ) fed with 0 or 4 mM caffeine. In agreement with the notion that many pro-apoptotic stimuli can promote Hpo or mammalian MST1/2 activation, 42,45,46 we found markedly higher levels of phospho-Hpo in extracts of eye imaginal disc isolated from larvae reared on a caffeine diet compared with controls (Figure 4c), indicating that caffeine promotes the activation ( = phosphorylation) of Hpo kinase.…”

Section: Resultsmentioning

confidence: 99%

“…42 This suggests that the contextdependent role of YAP in preventing or promoting stressinduced apoptosis is conserved in Drosophila Yki. The exact molecular nature of the context-dependent cue(s) that determine this 'apoptotic switch' 57 remain to be established, but are likely to involve posttranslational modification of Yki and/or p53, as well as the activation status of other signaling cascades, such as the JNK pathway 64 or c-Abl, 65 both of which have been shown to drive YAP-dependent apoptosis.…”

Section: Discussionmentioning

confidence: 99%

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The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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Cellular stress defense mechanisms have evolved to maintain homeostasis in response to a broad variety of environmental challenges. Stress signaling pathways activate multiple cellular programs that range from the activation of survival pathways to the initiation of cell death when cells are damaged beyond repair. To identify novel players acting in stress response pathways, we conducted a cell culture RNA interference (RNAi) screen using caffeine as a xenobiotic stress-inducing agent, as this compound is a well-established inducer of detoxification response pathways. Specifically, we examined how caffeine affects cell survival when Drosophila kinases and phosphatases were depleted via RNAi. Using this approach, we identified and validated 10 kinases and 4 phosphatases that are essential for cell survival under caffeine-induced stress both in cell culture and living flies. Remarkably, our screen yielded an enrichment of Hippo pathway components, indicating that this pathway regulates cellular stress responses. Indeed, we show that the Hippo pathway acts as a potent repressor of stress-induced cell death. Further, we demonstrate that Hippo activation is necessary to inhibit a pro-apoptotic program triggered by the interaction of the transcriptional co-activator Yki with the transcription factor p53 in response to a range of stress stimuli. Our in vitro and in vivo loss-of-function data therefore implicate Hippo signaling in the transduction of cellular survival signals in response to chemical stress. Throughout their lives, organisms are exposed to a wide range of harmful substances. These compounds, often referred to as xenobiotics, may enter the body through direct contact, inhalation or ingestion, and can originate from many sources including pharmaceuticals, pesticides, plant toxins and pollutants. The ubiquitous and varied nature of xenobiotic pressure is reflected in the complexity of conserved cellular defense mechanisms that respond to these chemical compounds, and metazoans have thus developed a range of pathways that activate survival responses or trigger programmed cell death to eliminate damaged cells. 1 Xenobiotic pathways control the expression and activation of heat shock proteins, oxidative stress components, DNA repair enzymes, hypoxia response factors and several groups of xenobiotic-metabolizing enzymes. In eukaryotes, environmental challenges that activate stress response programs are relayed through a complex signaling cascade. Some stress pathways respond to very specific compounds, whereas others, such as those depending on Mitogen-activated protein kinases, propagate stress signals from a broad spectrum of stimuli. 1-3 Despite the importance that stress response pathways play in pharmacology and toxicology, we still have a relatively poor understanding of the complex networks that launch these cellular defense systems.We performed a quantitative cell-culture RNA interference (RNAi) assay of Drosophila kinases and phosphatases to identify key regulators of stress response pathways that reac...

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Section: Discussionsupporting

confidence: 88%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

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“…It is widely accepted that p53 is a key determinant for cell death in response to anticancer drugs (Lowe et al, 1993(Lowe et al, , 1994. By using Drosophila genetics, Colombani et al (2006) discovered that Dmp53 (Drosophila melanogaster p53) activates Hippo, the Drosophila MST1 homolog, to induce cell death responses elicited by DNA-damaging ionizing radiation, suggesting a functional link between p53 and MST1. Moreover, it has been reported that p53-dependent apoptosis occurs through increasing oxidative stress (Johnson et al, 1996;Polyak et al, 1997;Li et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

et al. 2011

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Mammalian Ste20-like kinase-1 (MST1) kinase mediates H 2 O 2 -induced cell death by anticancer drugs such as cisplatin in a p53-dependent manner. However, the mechanism underlying MST1 activation by H 2 O 2 remains unknown. Here we show that peroxiredoxin-I (PRX-I) is an essential intermediate in H 2 O 2 -induced MST1 activation and cisplatin-induced cell death through p53. Cell stimulation with H 2 O 2 resulted in PRX-I oxidation to form homo-oligomers and interaction with MST1, leading to MST1 autophosphorylation and augmentation of kinase activity. In addition, RNA interference knockdown experiments indicated that endogenous PRX-I is required for H 2 O 2 -induced MST1 activation. Live-cell imaging showed H 2 O 2 generation by cisplatin treatment, which likewise caused PRX-I oligomer formation, MST1 activation and cell death. Cisplatin-induced PRX-I oligomer formation was not observed in embryonic fibroblasts obtained from p53-knockout mice, confirming the importance of p53. Indeed, ectopic expression of p53 induced PRX-I oligomer formation and cell death, both of which were cancelled by the antioxidant NAC. Moreover, we succeeded in reconstituting H 2 O 2 -induced MST1 activation in vitro, using purified PRX-I and MST1 proteins. Collectively, our results show a novel PRX-I function to cause cell death in response to high levels of oxidative stress by activating MST1, which underlies the p53-dependent cytotoxicity caused by anticancer agents.

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Regulation of organ size: Insights from the Drosophila Hippo signaling pathway

Kango‐Singh¹,

Singh²

2009

Developmental Dynamics

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Organ size control is a fundamental and core process of development of all multicellular organisms. One important facet of organ size control is the regulation of cell proliferation and cell death. Here we address the question, What are the developmental mechanisms that control intrinsic organ size? In several multicellular animals including humans and flies, organs develop according to an instructive model where proliferation is regulated by extracellular signals. However, the signals that regulate proliferation (and organ size) remain poorly understood. Recent data from flies have shed some light on the molecular mechanisms that regulate growth and size of organs. In this review, we will briefly discuss classic studies that revealed the mysteries of growth regulation. We will then focus on the recent findings from the Drosophila Hippo signaling pathway and its role in the regulation of organ size. Finally, we will discuss the mammalian Hippo pathway, and its implications in regulation of growth/proliferation during development and disease.

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Dmp53 Activates the Hippo Pathway to Promote Cell Death in Response to DNA Damage

Cited by 57 publications

References 32 publications

The Hippo pathway promotes cell survival in response to chemical stress

The Hippo pathway promotes cell survival in response to chemical stress

Oligomeric peroxiredoxin-I is an essential intermediate for p53 to activate MST1 kinase and apoptosis

Regulation of organ size: Insights from the Drosophila Hippo signaling pathway

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