17
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Hippo signaling: bridging the gap between cancer and neurodegenerative disorders

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          During development, regulation of organ size requires a balance between cell proliferation, growth and cell death. Dysregulation of these fundamental processes can cause a variety of diseases. Excessive cell proliferation results in cancer whereas excessive cell death results in neurodegenerative disorders. Many signaling pathways known-to-date have a role in growth regulation. Among them, evolutionarily conserved Hippo signaling pathway is unique as it controls both cell proliferation and cell death by a variety of mechanisms during organ sculpture and development. Neurodegeneration, a complex process of progressive death of neuronal population, results in fatal disorders with no available cure to date. During normal development, cell death is required for sculpting of an organ. However, aberrant cell death in neuronal cell population can result in neurodegenerative disorders. Hippo pathway has gathered major attention for its role in growth regulation and cancer, however, other functions like its role in neurodegeneration are also emerging rapidly. This review highlights the role of Hippo signaling in cell death and neurodegenerative diseases and provide the information on the chemical inhibitors employed to block Hippo pathway. Understanding Hippo mediated cell death mechanisms will aid in development of reliable and effective therapeutic strategies in future.

          Related collections

          Most cited references140

          • Record: found
          • Abstract: found
          • Article: found
          Is Open Access

          The amyloid hypothesis of Alzheimer's disease at 25 years

          Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control.

            The Hippo pathway plays a key role in organ size control by regulating cell proliferation and apoptosis in Drosophila. Although recent genetic studies have shown that the Hippo pathway is regulated by the NF2 and Fat tumor suppressors, the physiological regulations of this pathway are unknown. Here we show that in mammalian cells, the transcription coactivator YAP (Yes-associated protein), is inhibited by cell density via the Hippo pathway. Phosphorylation by the Lats tumor suppressor kinase leads to cytoplasmic translocation and inactivation of the YAP oncoprotein. Furthermore, attenuation of this phosphorylation of YAP or Yorkie (Yki), the Drosophila homolog of YAP, potentiates their growth-promoting function in vivo. Moreover, YAP overexpression regulates gene expression in a manner opposite to cell density, and is able to overcome cell contact inhibition. Inhibition of YAP function restores contact inhibition in a human cancer cell line bearing deletion of Salvador (Sav), a Hippo pathway component. Interestingly, we observed that YAP protein is elevated and nuclear localized in some human liver and prostate cancers. Our observations demonstrate that YAP plays a key role in the Hippo pathway to control cell proliferation in response to cell contact.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              Mechanisms of Hippo pathway regulation

              In this review, Meng et al. focus on recent developments in our understanding of the molecular actions of the core Hippo kinase cascade and discuss key open questions in Hippo pathway regulation and function.
                Bookmark

                Author and article information

                Journal
                Neural Regen Res
                Neural Regen Res
                NRR
                Neural Regeneration Research
                Wolters Kluwer - Medknow (India )
                1673-5374
                1876-7958
                April 2021
                09 October 2020
                : 16
                : 4
                : 643-652
                Affiliations
                [1 ]Department of Biology, University of Dayton, Dayton, OH, USA
                [2 ]Medical Candidate, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
                [3 ]Premedical Program, University of Dayton, Dayton, OH, USA
                [4 ]Center for Tissue Regeneration and Engineering at Dayton (TREND), University of Dayton, Dayton, OH, USA
                [5 ]The Integrative Science and Engineering Center, University of Dayton, Dayton, OH, USA
                [6 ]Center for Genomic Advocacy (TCGA), Indiana State University, Terre Haute, IN, USA
                Author notes
                [* ] Correspondence to: Amit Singh, asingh1@ 123456udayton.edu .
                [#]

                These authors contributed equally to this work.

                Author contributions: Amit S conceived the manuscript. Amit S, NG, AVC, PD, Aditi S were responsible for manuscript writing, image preparation and editing .

                Author information
                https://orcid.org/0000-0002-2962-2255
                Article
                NRR-16-643
                10.4103/1673-5374.295273
                8067938
                33063715
                6e787f4e-6782-4e45-b59b-93697587a245
                Copyright: © 2021 Neural Regeneration Research

                This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.

                History
                : 26 May 2020
                : 29 May 2020
                : 13 July 2020
                Categories
                Review

                animal models,cell death mechanisms,cell-signaling,chemical inhibitors,drosophila eye,hippo pathway,neurodegeneration,neurological diseases,therapeutic targets

                Comments

                Comment on this article