Abstract:The pulmonary alveolar epithelium undergoes extensive regeneration in response to lung injuries, including lung resection. In recent years, our understanding of cell lineage relationships in the pulmonary alveolar epithelium has improved significantly. However, the molecular and cellular mechanisms that regulate pneumonectomy (PNX)-induced alveolar regeneration remain largely unknown. In this study, we demonstrate that mechanical-tension-induced YAP activation in alveolar stem cells plays a major role in promo… Show more
“…Briefly, mice were mechanically ventilated for 10 minutes with 100% oxygen. The tracheal tube was then clamped for 10 a role for YAP signaling in alveolar regeneration in this context (59). In the current study, we show that loss of CLDN18 leads to YAP activation and progenitor expansion in distal lung in the absence of injury, uncovering a role for YAP signaling in regulating distal lung epithelial progenitor maintenance and proliferation downstream of CLDN18 and suggesting that CLDN18 regulates AT2 cell quiescence by restricting YAP activity.…”
Section: Tissue Preparation and Morphological Analysis Tissues Harvementioning
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
“…Briefly, mice were mechanically ventilated for 10 minutes with 100% oxygen. The tracheal tube was then clamped for 10 a role for YAP signaling in alveolar regeneration in this context (59). In the current study, we show that loss of CLDN18 leads to YAP activation and progenitor expansion in distal lung in the absence of injury, uncovering a role for YAP signaling in regulating distal lung epithelial progenitor maintenance and proliferation downstream of CLDN18 and suggesting that CLDN18 regulates AT2 cell quiescence by restricting YAP activity.…”
Section: Tissue Preparation and Morphological Analysis Tissues Harvementioning
Claudins, the integral tight junction (TJ) proteins that regulate paracellular permeability and cell polarity, are frequently dysregulated in cancer; however, their role in neoplastic progression is unclear. Here, we demonstrated that knockout of Cldn18, a claudin family member highly expressed in lung alveolar epithelium, leads to lung enlargement, parenchymal expansion, increased abundance and proliferation of known distal lung progenitors, the alveolar epithelial type II (AT2) cells, activation of Yes-associated protein (YAP), increased organ size, and tumorigenesis in mice. Inhibition of YAP decreased proliferation and colony-forming efficiency (CFE) of Cldn18 -/-AT2 cells and prevented increased lung size, while CLDN18 overexpression decreased YAP nuclear localization, cell proliferation, CFE, and YAP transcriptional activity. CLDN18 and YAP interacted and colocalized at cell-cell contacts, while loss of CLDN18 decreased YAP interaction with Hippo kinases p-LATS1/2. Additionally, Cldn18 -/-mice had increased propensity to develop lung adenocarcinomas (LuAd) with age, and human LuAd showed stage-dependent reduction of CLDN18.1. These results establish CLDN18 as a regulator of YAP activity that serves to restrict organ size, progenitor cell proliferation, and tumorigenesis, and suggest a mechanism whereby TJ disruption may promote progenitor proliferation to enhance repair following injury.
“…As a result, epithelial differentiation occurs on the ocular surface indicating a causal link between inflammation-induced corneal disorders and tissue mechanics [111]. Yap activation was also observed to underlie mechanical-tension induced regeneration of lung pulmonary alveolar epithelium [112]. This suggests that appropriate spatio-temporal control of tissue mechanics is key to lung repair and its deregulation may be a reason for incomplete repair after injury.…”
Human tissues are remarkably adaptable and robust, harboring the collective ability to detect and respond to external stresses while maintaining tissue integrity. Following injury, many tissues have the capacity to repair the damage - and restore form and function - by deploying cellular and molecular mechanisms reminiscent of developmental programs. Indeed, it is increasingly clear that cancer and chronic conditions that develop with age arise as a result of cells and tissues re-implementing and deregulating a selection of developmental programs. Therefore, understanding the fundamental molecular mechanisms that drive cell and tissue responses is a necessity when designing therapies to treat human conditions. Extracellular matrix stiffness synergizes with chemical cues to drive single cell and collective cell behavior in culture and acts to establish and maintain tissue homeostasis in the body. This review will highlight recent advances that elucidate the impact of matrix mechanics on cell behavior and fate across these length scales during times of homeostasis and in disease states.
“…Recent studies have shown that Hippo pathway does not exclusively regulate YAP/TAZ phosphorylation and nuclear translation. Instead, other signaling pathways also induce YAP/TAZ activation and nuclear localization at transcriptional and post-translational levels, such as Wnt/β-catenin signaling pathway [22, 23], JNK signaling pathway [24] and Rho-GTPs signaling pathways [25], even in tumor cell energy metabolism [26, 27]. Thus, YAP/TAZ function as key nodes of multiple signaling pathways and serve as nuclear and transcriptional mediator to directly mediate target genes transcription in most cancer cells.Fig.…”
In contrast to normal cells, which use the aerobic oxidation of glucose as their main energy production method, cancer cells prefer to use anaerobic glycolysis to maintain their growth and survival, even under normoxic conditions. Such tumor cell metabolic reprogramming is regulated by factors such as hypoxia and the tumor microenvironment. In addition, dysregulation of certain signaling pathways also contributes to cancer metabolic reprogramming. Among them, the Hippo signaling pathway is a highly conserved tumor suppressor pathway. The core oncosuppressive kinase cascade of Hippo pathway inhibits the nuclear transcriptional co-activators YAP and TAZ, which are the downstream effectors of Hippo pathway and oncogenic factors in many solid cancers. YAP/TAZ function as key nodes of multiple signaling pathways and play multiple regulatory roles in cancer cells. However, their roles in cancer metabolic reprograming are less clear. In the present review, we examine progress in research into the regulatory mechanisms of YAP/TAZ on glucose metabolism, fatty acid metabolism, mevalonate metabolism, and glutamine metabolism in cancer cells. Determining the roles of YAP/TAZ in tumor energy metabolism, particularly in relation to the tumor microenvironment, will provide new strategies and targets for the selective therapy of metabolism-related cancers.
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