Non-cell autonomous control of apoptosis by ligand-independent Hedgehog signaling in Drosophila |
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Authors: | A E Christiansen T Ding Y Fan H K Graves H-M Herz J L Lindblad A Bergmann |
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Institution: | 1.Department of Biochemistry and Molecular Biology, The University of Texas M. D. Anderson Cancer Center, Genes & Development Graduate Program, 1515 Holcombe Boulevard—Unit 1000, Houston, TX 77030, USA;2.Department of Cancer Biology, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA;3.Stowers Institute for Medical Research, Kansas City, MO 64110, USA |
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Abstract: | Hedgehog (Hh) signaling is important for development and homeostasis in vertebrates and invertebrates. Ligand-independent, deregulated Hh signaling caused by loss of negative regulators such as Patched causes excessive cell proliferation, leading to overgrowth in Drosophila and tumors in humans, including basal-cell carcinoma and medulloblastoma. We show that in Drosophila deregulated Hh signaling also promotes cell survival by increasing the resistance to apoptosis. Surprisingly, cells with deregulated Hh activity do not protect themselves from apoptosis; instead, they promote cell survival of neighboring wild-type cells. This non-cell autonomous effect is mediated by Hh-induced Notch signaling, which elevates the protein levels of Drosophila inhibitor of apoptosis protein-1 (Diap-1), conferring resistance to apoptosis. In summary, we demonstrate that deregulated Hh signaling not only promotes proliferation but also cell survival of neighboring cells. This non-cell autonomous control of apoptosis highlights an underappreciated function of deregulated Hh signaling, which may help to generate a supportive micro-environment for tumor development. |
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Keywords: | Hedgehog Notch non-cell autonomous effects cell survival Drosophila inhibitor of apoptosis |
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