YAP: At the crossroad between transformation and tumor suppression

Bertini, Efrem; Oka, Tsutomu; Sudol, Marius; Strano, Sabrina; Blandino, Giovanni

doi:10.4161/cc.8.1.7259

Cited by 106 publications

(114 citation statements)

References 55 publications

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“…[51][52][53][54][55][56][57] In many of these cases, this pro-apoptotic function has been linked to YAP's ability to bind to p73 and promote p73-dependent gene expression. As Drosophila p53 is most closely related to mammalian p73, we tested the involvement of Drosophila p53 in caffeine-induced toxicity.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

The Hippo pathway promotes cell survival in response to chemical stress

Cara

Maile²,

Parsons

et al. 2015

Cell Death Differ

View full text Add to dashboard Cite

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“…YAP acts, in part, via binding and regulating the transcription factor p73 (16,17). However, YAP is a complex signaling molecule that can exhibit the properties of an oncogene or a tumor suppressor, depending upon the cellular context (18). Moreover, the descriptions of its mechanism of action remain somewhat contradictory.…”

Section: Discussionmentioning

confidence: 99%

“…The pathways controlled by activated LATS are only now being revealed and appear to involve direct phosphorylation of the transcriptional coactivator YAP (15), which controls transcription factors such as the tumor suppressor p73 (16,17). However, the function of YAP remains somewhat controversial, as it appears to be able to act as an oncogene or a tumor suppressor, depending upon the cellular context (18).…”

mentioning

confidence: 99%

Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions

Donninger

Allen²,

Henson

et al. 2011

Journal of Biological Chemistry

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The RASSF1A tumor suppressor binds and activates proapoptotic MST kinases. The Salvador adaptor protein couples MST kinases to the LATS kinases to form the hippo pathway. Upon activation by RASSF1A, LATS1 phosphorylates the transcriptional regulator YAP, which binds to p73 and activates its proapoptotic effects. However, although serving as an adaptor for MST and LATS, Salvador can also bind RASSF1A. The functional role of the RASSF1A/Salvador interaction is unclear. Although Salvador is a novel tumor suppressor in Drosophila and mice, its role in human systems remains largely unknown. Here we show that Salvador promotes apoptosis in human cells and that Salvador inactivation deregulates the cell cycle and enhances the transformed phenotype. Moreover, we show that although the salvador gene is seldom mutated or epigenetically inactivated in human cancers, it is frequently down-regulated posttranscriptionally. Surprisingly, we also find that although RASSF1A requires the presence of Salvador for full apoptotic activity and to activate p73, this effect does not require a direct interaction of RASSF1A with MST kinases or the activation of the hippo pathway. Thus, we confirm a role for Salvador as a human tumor suppressor and RASSF1A effector and show that Salvador allows RASSF1A to modulate p73 independently of the hippo pathway.

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“…On the basis of our analysis, we propose a model of interactions (Fig. 4) based on both previous data (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29) and the interactions we found. This example provides evidence that our approach has identified "-omic" linkages that, although new, have basis in biochemical rationale and are supported, in part, by past research (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 85%

Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures

Federici

Gao

Slawek

et al. 2013

Molecular Cancer Research

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The NCI-60 cell line set is likely the most molecularly profiled set of human tumor cell lines in the world. However, a critical missing component of previous analyses has been the inability to place the massive amounts of "-omic" data in the context of functional protein signaling networks, which often contain many of the drug targets for new targeted therapeutics. We used reverse-phase protein array (RPPA) analysis to measure the activation/ phosphorylation state of 135 proteins, with a total analysis of nearly 200 key protein isoforms involved in cell proliferation, survival, migration, adhesion, etc., in all 60 cell lines. We aggregated the signaling data into biochemical modules of interconnected kinase substrates for 6 key cancer signaling pathways: AKT, mTOR, EGF receptor (EGFR), insulin-like growth factor-1 receptor (IGF-1R), integrin, and apoptosis signaling. The net activation state of these protein network modules was correlated to available individual protein, phosphoprotein, mutational, metabolomic, miRNA, transcriptional, and drug sensitivity data. Pathway activation mapping identified reproducible and distinct signaling cohorts that transcended organ-type distinctions. Direct correlations with the protein network modules involved largely protein phosphorylation data but we also identified direct correlations of signaling networks with metabolites, miRNA, and DNA data.

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YAP: At the crossroad between transformation and tumor suppression

Cited by 106 publications

References 55 publications

The Hippo pathway promotes cell survival in response to chemical stress

The Hippo pathway promotes cell survival in response to chemical stress

Salvador Protein Is a Tumor Suppressor Effector of RASSF1A with Hippo Pathway-independent Functions

Systems Analysis of the NCI-60 Cancer Cell Lines by Alignment of Protein Pathway Activation Modules with “-OMIC” Data Fields and Therapeutic Response Signatures

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