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\"This guide provides everything you need to know to discover the South's best-kept secrets of winter recreation: snow-covered mountains, remote yet accessible trails, high-quality downhill and cross-country skiing, sparkling resorts and peaceful cabins, and of course, southern hospitality. Randy Johnson is a knowledgeable guide who shares his years of experience enjoying the winter wonders from the mountains of western Maryland down the Appalachian corridor all the way to northern Alabama\"-- Provided by publisher.

Key Points The Hippo pathway is an emerging tumour suppressor pathway that regulates cell proliferation, stem cell functions and organ size. The Hippo pathway transduces signals from diverse transmembrane inputs such as the cell adhesion and cell polarity receptors E-cadherin, FAT and Crumbs, as well as G protein-coupled receptors (GPCRs), through a kinase cascade that regulates the subcellular localization and activities of the transcriptional co-activators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ). YAP and TAZ promote cell proliferation and organ growth. Hyperactivation or overexpression of YAP in mouse models causes overgrowth of various organs and can lead to the development of cancer in the liver, skin and intestine. YAP and TAZ act as oncogenes and are hyperactivated or overexpressed with a high frequency in many common human cancers. YAP and TAZ promote multiple cancer cell phenotypes, including proliferation, migration and resistance to apoptosis. Direct or indirect inhibition of YAP and TAZ is a promising novel targeted approach for cancer therapy, and small-molecule modulators of the Hippo pathway have been discovered. Pharmacological modulation of YAP has been shown to be effective for reverting YAP-driven overgrowth phenotypes in mouse models. Further research is required to test whether small molecules targeting YAP and TAZ are active against human cancer cells and in mouse models that more accurately recapitulate the genetic defects of human tumours. By contrast, drugs that stimulate YAP and TAZ activity may be useful for stem cell expansion and tissue repair following injury. YAP is activated during the regeneration of the intestinal epithelium, and experimental activation of YAP promotes the capacity of the mouse heart to regenerate. The Hippo signalling pathway is an emerging growth control pathway with roles in organ growth control, stem cell function, regeneration and tumour suppression. Here, Johnson and Halder review the regulation and functions of the Hippo signalling pathway, focusing on its potential to be therapeutically targeted in the treatment of cancer as well as tissue repair and regeneration following injury. The Hippo signalling pathway is an emerging growth control and tumour suppressor pathway that regulates cell proliferation and stem cell functions. Defects in Hippo signalling and hyperactivation of its downstream effectors Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) contribute to the development of cancer, which suggests that pharmacological inhibition of YAP and TAZ activity may be an effective anticancer strategy. Conversely, YAP and TAZ can also have beneficial roles in stimulating tissue repair and regeneration following injury, so their activation may be therapeutically useful in these contexts. A complex network of intracellular and extracellular signalling pathways that modulate YAP and TAZ activities have recently been identified. Here, we review the regulation of the Hippo signalling pathway, its functions in normal homeostasis and disease, and recent progress in the identification of small-molecule pathway modulators.

When Hall of Fame pitcher and five-time Cy Young Award winner Randy Johnson seamlessly transitioned from his legendary playing career to his lifelong passion - photography - his understanding of timing and rhythm in baseball translated to his ability to capture dynamic and decisive moments in his photographs. Travelling throughout Africa with camera in hand, he has documented the untamed beauty of this vast continent's landscapes, the diversity of its wildlife, and the vibrant lives of the people who inhabit and care for this land. Together these 100 images become a testament to Africa's diverse tapestry of life.

Damaged acinar cells play a passive role in activating pancreatic stellate cells (PSCs) via recruitment of immune cells that subsequently activate PSCs. However, whether acinar cells directly contribute to PSC activation is unknown. Here, we report that the Hippo pathway, a well-known regulator of proliferation, is essential for suppression of expression of inflammation and fibrosis-associated genes in adult pancreatic acinar cells. Hippo inactivation in acinar cells induced yes-associated protein 1 (YAP1)/transcriptional coactivator with PDZ binding motif (TAZ)-dependent, irreversible fibrosis and inflammation, which was initiated by Hippo-mediated acinar-stromal communications and ameliorated by blocking YAP1/TAZ target connective tissue growth factor (CTGF). Hippo disruption promotes acinar cells to secrete fibroinflammatory factors and induce stromal activation, which precedes acinar proliferation and metaplasia. We found that Hippo disruption did not induce cell-autonomous proliferation but primed acinar cells to exogenous pro-proliferative stimuli, implying a well-orchestrated scenario in which Hippo signaling acts as an intrinsic link to coordinate fibroinflammatory response and proliferation for maintenance of the tissue integrity. Our findings suggest that the fibroinflammatory program in pancreatic acinar cells is suppressed under normal physiological conditions. While transient activation of inflammatory gene expression during tissue injury may contribute to the control of damage and tissue repair, its persistent activation may result in tissue fibrosis and failure of regeneration.

The Hippo pathway was discovered as a conserved tumour suppressor pathway restricting cell proliferation and apoptosis. However, the upstream signals that regulate the Hippo pathway in the context of organ size control and cancer prevention are largely unknown. Here, we report that glucose, the ubiquitous energy source used for ATP generation, regulates the Hippo pathway downstream effector YAP. We show that both the Hippo pathway and AMP-activated protein kinase (AMPK) were activated during glucose starvation, resulting in phosphorylation of YAP and contributing to its inactivation. We also identified glucose-transporter 3 ( GLUT3 ) as a YAP-regulated gene involved in glucose metabolism. Together, these results demonstrate that glucose-mediated energy homeostasis is an upstream event involved in regulation of the Hippo pathway and, potentially, an oncogenic function of YAP in promoting glycolysis, thereby providing an exciting link between glucose metabolism and the Hippo pathway in tissue maintenance and cancer prevention. In two related papers, Chen and colleagues and Guan and colleagues report a crucial role for the AMPK and Hippo pathways in glucose homeostasis. Starvation triggers AMPK-mediated phosphorylation and inactivation of YAP.

The mammalian liver has a remarkable capacity for repair following injury. Removal of up to two-third of liver mass results in a series of events that include extracellular matrix remodeling, coordinated hepatic cell cycle re-entry, restoration of liver mass and tissue remodeling to return the damaged liver to its normal state. Although there has been considerable advancement of our knowledge concerning the regenerative capacity of the mammalian liver, many outstanding questions remaining, such as: how does the regenerating liver stop proliferating when appropriate mass is restored and how do these mechanisms relate to normal regulation of organ size during development? Hippo pathway has been proposed to be central in mediating both events: organ size control during development and following regeneration. In this report, we examined the role of Yap and Taz, key components of the Hippo pathway in liver organ size regulation, both in the context of development and homeostasis. Our studies reveal that contrary to the current paradigms that Yap/Taz are not required for developmental regulation of liver size but are required for proper liver regeneration. In livers depleted of Yap and Taz, liver mass is elevated in neonates and adults. However, Yap/Taz-depleted livers exhibit profound defects in liver regeneration, including an inability to restore liver mass and to properly coordinate cell cycle entry. Taken together, our results highlight requirements for the Hippo pathway during liver regeneration and indicate that there are additional pathways that cooperate with Hippo signaling to control liver size during development and in the adult. Liver regeneration: The pathway to regrowth Liver cancer treatment could benefit from new findings detailing how a signalling pathway helps the liver to regenerate. Mammalian livers have an impressive ability to regrow after injury, and the Hippo signalling pathway has been identified as a key mediator involved in both healing the liver and controlling its size. Randy Johnson at the MD Anderson Cancer Center in Houston, USA, and co-workers generated mice lacking two coactivator proteins from the Hippo pathway called Yap and Taz. They found that the mutant mice showed no difference in liver development, but were less able to completely recover their liver mass after two-thirds of it was removed. This suggests that Yap and Taz are required to mount efficient regenerative responses, for example to cancer. Therapies that target these proteins could potentially inhibit liver cancer tumour progression.

Genetic regulation of mammalian heart size is poorly understood. Hippo signaling represents an organ-size control pathway in Drosophila, where it also inhibits cell proliferation and promotes apoptosis in imaginal discs. To determine whether Hippo signaling controls mammalian heart size, we inactivated Hippo pathway components in the developing mouse heart. Hippo-deficient embryos had overgrown hearts with elevated cardiomyocyte proliferation. Gene expression profiling and chromatin immunoprecipitation revealed that Hippo signaling negatively regulates a subset of Wnt target genes. Genetic interaction studies indicated that β-catenin heterozygosity suppressed the Hippo cardiomyocyte overgrowth phenotype. Furthermore, the Hippo effector Yap interacts with β-catenin on Sox2 and Snai2 genes. These data uncover a nuclear interaction between Hippo and Wnt signaling that restricts cardiomyocyte proliferation and controls heart size.

Reactive oxygen species (ROS) production in phagocytes is a major defense mechanism against pathogens. However, the cellular self-protective mechanism against such potential damage from oxidative stress remains unclear. Here we show that the kinases Mst1 and Mst2 (Mst1/2) sense ROS and maintain cellular redox balance by modulating the stability of antioxidant transcription factor Nrf2. Site-specific ROS release recruits Mst1/2 from the cytosol to the phagosomal or mitochondrial membrane, with ROS subsequently activating Mst1/2 to phosphorylate kelch like ECH associated protein 1 (Keap1) and prevent Keap1 polymerization, thereby blocking Nrf2 ubiquitination and degradation to protect cells against oxidative damage. Treatment with the antioxidant N-acetylcysteine disrupts ROS-induced interaction of Mst1/2 with phagosomes or mitochondria, and thereby diminishes the Mst-Nrf2 signal. Consistently, loss of Mst1/2 results in increased oxidative injury, phagocyte ageing and death. Thus, our results identify the Mst-Nrf2 axis as an important ROS-sensing and antioxidant mechanism during an antimicrobial response. Immune cells produce reactive oxygen species (ROS) to eliminate pathogens, but cell-spontaneous death and ageing may also be induced. Here the authors show that, upon sensing ROS, Mst1/2 kinases modulate the activity of Nrf2 transcription factor and downstream genetic programs to protect mouse macrophages from death and ageing.

BackgroundGastric adenocarcinoma (GAC) is a lethal disease with limited therapeutic options. Genetic alterations in chromatin remodelling gene AT-rich interactive domain 1A (ARID1A) and mTOR pathway activation occur frequently in GAC. Targeting the mechanistic target of rapamycin (mTOR) pathway in unselected patients has failed to show survival benefit. A deeper understanding of GAC might identify a subset that can benefit from mTOR inhibition.MethodsGenomic alterations in ARID1A were analysed in GAC. Mouse gastric epithelial cells from CK19-Cre-Arid1Afl/fl and wild-type mice were used to determine the activation of oncogenic genes due to loss of Arid1A. Functional studies were performed to determine the significance of loss of ARID1A and the sensitivity of ARID1A-deficient cancer cells to mTOR inhibition in GAC.ResultsMore than 30% of GAC cases had alterations (mutations or deletions) of ARID1A and ARID1A expression was negatively associated with phosphorylation of S6 and SOX9 in GAC tissues and patient-derived xenografts (PDXs). Activation of mTOR signalling (increased pS6) and SOX9 nuclear expression were strongly increased in Arid1A−/− mouse gastric tissues which could be curtailed by RAD001, an mTOR inhibitor. Knockdown of ARID1A in GAC cell lines increased pS6 and nuclear SOX9 and increased sensitivity to an mTOR inhibitor which was further amplified by its combination with fluorouracil both in vitro and in vivo in PDXs.ConclusionsThe loss of ARID1A activates pS6 and SOX9 in GAC, which can be effectively targeted by an mTOR inhibitor. Therefore, our studies suggest a new therapeutic strategy of clinically targeting the mTOR pathway in patients with GAC with ARID1A deficiency.