How size is controlled: From Hippos to Yorkies

Fred Hutchinson Cancer Research Center, Seattle, Washington, United States
Nature Cell Biology (Impact Factor: 19.68). 12/2007; 9(11):1225-7. DOI: 10.1038/ncb1107-1225
Source: PubMed


How do developing organs sense and limit their size? The recently discovered Hippo pathway might have a critical role in controlling organ size and homeostasis in many organisms from Drosophila to mammals.

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Available from: Laura Buttitta, May 09, 2014
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    • "The molecular details of the Hippo pathway, although still emerging, have been reviewed elsewhere (e.g. Buttitta and Edgar, 2007; Grusche et al., 2010b; Halder and Johnson, 2011; Pan, 2007; Reddy and Irvine, 2008), and will not be reiterated, except to say that a major source of input into the pathway is the cell surface protocadherin Fat, and the major intracellular target of Hippo signaling seems to be the growth-stimulating transcriptional coactivator Yorkie (Yki; the vertebrate homolog of YAP), which Hippo signaling inactivates. Precisely what the crucial targets of Yki are is unknown, but recent studies suggest that, like GDF11, its functions include the regulation of self-renewal, and not just the rate at which cells traverse the cell cycle (Halder and Johnson, 2011). "
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    ABSTRACT: Systems biology seeks not only to discover the machinery of life but to understand how such machinery is used for control, i.e., for regulation that achieves or maintains a desired, useful end. This sort of goal-directed, engineering-centered approach also has deep historical roots in developmental biology. Not surprisingly, developmental biology is currently enjoying an influx of ideas and methods from systems biology. This Review highlights current efforts to elucidate design principles underlying the engineering objectives of robustness, precision, and scaling as they relate to the developmental control of growth and pattern formation. Examples from vertebrate and invertebrate development are used to illustrate general lessons, including the value of integral feedback in achieving set-point control; the usefulness of self-organizing behavior; the importance of recognizing and appropriately handling noise; and the absence of "free lunch." By illuminating such principles, systems biology is helping to create a functional framework within which to make sense of the mechanistic complexity of organismal development.
    Preview · Article · Mar 2011 · Cell
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    • "Hippo, a kinase, modulates a chain of events that lead to expression of genes involved in cell proliferation and growth regulation (Badouel et al. 2009). Study of the Hippo pathway in fl ies has identifi ed close similarities to the same pathway in mammalian species (Buttitta and Edgar 2007). In fl ies, mutations in hippo can lead to epithelial cell proliferation in several tissues—and play a role in managing apoptosis—so cancer researchers can add Drosophila to their arsenal as a model for studying control of cell proliferation (Gilbert 2008). "
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    ABSTRACT: Invertebrate animals have been used as medicinals for 4,000 years and have served as models for research and teaching since the late 1800s. Interest in invertebrate models has increased over the past several decades as the research community has responded to public concerns about the use of vertebrate animals in research. As a result, invertebrates are being evaluated and recognized as models for many diseases and conditions. Their use has led to discoveries in almost every area of biology and medicine--from embryonic development to aging processes. Species range from terrestrial invertebrates such as nematodes and insects to freshwater and marine life including planarians, crustaceans, molluscs, and many others. The most often used models are the fruit fly Drosophila melanogaster and the minuscule nematode Caenorhabditis elegans. Topics in this article are categorized by biologic system, process, or disease with discussion of associated invertebrate models. Sections on bioactive products discovered from invertebrates follow the models section, and the article concludes with uses of invertebrates in teaching. The models reviewed can serve as references for scientists, researchers, veterinarians, institutional animal care and use committees (IACUCs), and others interested in alternatives to vertebrate animals.
    Full-text · Article · Jan 2011 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
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    • "Overexpression of the Yki/Scalloped target genes partly explains the cellular proliferation and inhibition of apoptosis, and malfunction of the upstream Hippo signaling kinases has been shown to cause tissue overgrowth or organ enlargement (Huang et al., 2005; Buttitta and Edgar, 2007; Pan, 2007; Yin and Pan, 2007). "
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    ABSTRACT: Yes-associated protein (YAP) is a downstream effector of the Hippo signaling pathway, which controls organ expansion and tissue development. We have recently defined the tumorigenic potential and clinical significance of the YAP1 oncogene in human hepatocellular carcinoma (HCC). The present study aims to define the tumorigenic properties of YAP in HCC and elucidate the related downstream signaling mechanism. In a gain-of-function study, we demonstrated that ectopic increased expression of YAP in the immortalized non-tumorigenic hepatocyte cell line MIHA confers tumorigenic and metastatic potentials, as evidenced by (1) enhanced aptitudes in cell viability, anchorage-independent growth, migration and invasion; (2) tumor formation in a xenograft mouse model; and (3) induction of HCC biomarker α-fetoprotein and activation of mitogen-activated protein kinase. Furthermore, we have identified AXL, a receptor tyrosine kinase, as a key downstream target that drives YAP-dependent oncogenic functions. RNAi-mediated knockdown of AXL expression decreased the ability of YAP-expressing MIHA cells and of the primary HCC cell line to proliferate and invade. These results indicate that AXL is a mediator of YAP-dependent oncogenic activities and implicates it as a potential therapeutic target for HCC.
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