PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop

Lapi, Eleonora; Agostino, Silvia Di; Donzelli, Sara; Gal, Hilah; Domany, Eytan; Rechavi, Gideon; Pandolfi, Pier Paolo; Givol, David; Strano, Sabrina; Lü, Xin; Blandino, Giovanni

doi:10.1016/j.molcel.2008.11.019

Cited by 220 publications

(236 citation statements)

References 26 publications

(48 reference statements)

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“…71 Interestingly, YAP also promotes interaction between p73 and the p300 acetyltransferase, with implications on p73 transcriptional activity. 72 As p300-dependent acetylation is also linked with p73 stability, 73 YAP-dependent p73-p300 association could be functional first for p73 stability, and then for p73 transcriptional activity. The adaptor YAP is also a direct target of the PI3K/Akt signaling pathway, 74 which has a central role in growth and proliferation in normal cells and in tumors, contributing to cell survival by blocking apoptosis.…”

Section: Mdm2mentioning

confidence: 99%

“…In fact, all three p53-family proteins can be recruited to subnuclear structures called PML nuclear bodies (PML-NB), and association with PML promotes their modification, stabilization, and activation. 72,89,90 A number of common interactors of p53-family proteins are also found in PML-NBs, including the acetylase p300, the protein kinase Hipk2, and the transcriptional repressor Daxx, and hence PML-dependent recruitment to NBs might regulate formation of specific protein complexes. Notably, PML facilitates the interaction of YAP with p73 (see above), stimulates the recruitment of p300 on p73, and promotes p73-dependent transactivation of pro-apoptotic target genes after DNA damage.…”

Section: And References Therein)mentioning

confidence: 99%

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p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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The tumor suppressor p53 is a central hub in a molecular network controlling cell proliferation and death in response to potentially oncogenic conditions, and a wide array of covalent modifications and protein interactions modulate the nuclear and cytoplasmic activities of p53. The p53 relatives, p73 and p63, are entangled in the same regulatory network, being subject at least in part to the same modifications and interactions that convey signals on p53, and actively contributing to the resulting cellular output. The emerging picture is that of an interconnected pathway, in which all p53-family proteins are involved in the response to oncogenic stress and physiological inputs. Therefore, common and specific interactors of p53-family proteins can have a wide effect on function and dysfunction of this pathway. Many years of research have uncovered an impressive number of p53-interacting proteins, but much less is known about protein interactions of p63 and p73. Yet, many interactors may be shared by multiple p53-family proteins, with similar or different effects. In this study we review shared interactors of p53-family proteins with the aim to encourage research into this field; this knowledge promises to unveil regulatory elements that could be targeted by a new generation of molecules, and allow more efficient use of currently available drugs for cancer treatment.

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Section: Mdm2mentioning

confidence: 99%

Section: And References Therein)mentioning

confidence: 99%

p53-family proteins and their regulators: hubs and spokes in tumor suppression

2010

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“…Yes-associated protein (YAP) is a pro-apoptotic transcriptional coactivator that acts within the Hippo pathway and regulates cell proliferation, cell differentiation, spatial organ patterning and tissue regeneration [26]. Furthermore, YAP potentiates p73 function as a transcription factor [27–29]. Additionally, YAP has been reported as a potential integrator of cell death processes and autophagy during cellular stress [30–32].…”

Section: Introductionmentioning

confidence: 99%

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

et al. 2018

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B cells are a target of Salmonella infection, allowing bacteria survival without inducing pyroptosis. This event is due to downregulation of Nlrc4 expression and lack of inflammasome complex activation, which impairs the secretion of IL-1β. YAP phosphorylation is required for downregulation of Nlrc4 in B cells during Salmonella infection; however, the microorganism’s mechanisms underlying the inhibition of the NLRC4 inflammasome in B cells are not fully understood. Our findings demonstrate that the Salmonella effector SopB triggers a signaling cascade involving PI3K, PDK1 and mTORC2 that activates Akt with consequent phosphorylation of YAP. When we deleted sopB in Salmonella, infected B cells that lack Rictor, or inhibited the signaling cascade using a pharmacological approach, we were able to restore the function of the NLRC4 inflammasome in B cells and the ability to control the infection. Furthermore, B cells from infected mice exhibited activation of Akt and YAP phosphorylation, suggesting that Salmonella also triggers this pathway in vivo. In summary, our data demonstrate that the Salmonella effector inositide phosphate phosphatase SopB triggers the PI3K-Akt-YAP pathway to inhibit the NLRC4 inflammasome in B cells. This study provides further evidence that Salmonella triggers cellular mechanisms in B lymphocytes to manipulate the host environment by turning it into a survival niche to establish a successful infection.

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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%

“…[10][11][12] In contrast, when cells are chemically stressed via cisplatin treatment, YAP binds to and stabilizes the p53 family member p73, thus promoting pro-apoptotic gene expression. [52][53][54] Similar to the YAP/TEAD pro-growth/survival function, the pro-apoptotic role of YAP/p73 is suppressed by the core Hippo signaling cascade. 51,56 Drosophila has a single member of the p53 family, p53, 31,33 which regulates cell death and differentiation pathways.…”

Section: Discussionmentioning

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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PML, YAP, and p73 Are Components of a Proapoptotic Autoregulatory Feedback Loop

Cited by 220 publications

References 26 publications

p53-family proteins and their regulators: hubs and spokes in tumor suppression

p53-family proteins and their regulators: hubs and spokes in tumor suppression

SopB activates the Akt-YAP pathway to promote Salmonella survival within B cells

The Hippo pathway promotes cell survival in response to chemical stress

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