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      The E3 ligase APC/C(Cdh1) promotes ubiquitylation-mediated proteolysis of PAX3 to suppress melanocyte proliferation and melanoma growth.

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          Abstract

          The anaphase-promoting complex or cyclosome with the subunit Cdh1 (APC/C(Cdh1)) is an E3 ubiquitin ligase involved in the control of the cell cycle. Here, we identified sporadic mutations occurring in the genes encoding APC components, including Cdh1, in human melanoma samples and found that loss of APC/C(Cdh1) may promote melanoma development and progression, but not by affecting cell cycle regulatory targets of APC/C. Most of the mutations we found in CDH1 were those associated with ultraviolet light (UV)-induced melanomagenesis. Compared with normal human skin tissue and human or mouse melanocytes, the abundance of Cdh1 was decreased and that of the transcription factor PAX3 was increased in human melanoma tissue and human or mouse melanoma cell lines, respectively; Cdh1 abundance was further decreased with advanced stages of human melanoma. PAX3 was a substrate of APC/C(Cdh1) in melanocytes, and APC/C(Cdh1)-mediated ubiquitylation marked PAX3 for proteolytic degradation in a manner dependent on the D-box motif in PAX3. Either mutating the D-box in PAX3 or knocking down Cdh1 prevented the ubiquitylation and degradation of PAX3 and increased proliferation and melanin production in melanocytes. Knocking down Cdh1 in melanoma cells in culture or before implantation in mice promoted doxorubicin resistance, whereas reexpressing wild-type Cdh1, but not E3 ligase-deficient Cdh1 or a mutant that could not interact with PAX3, restored doxorubicin sensitivity in melanoma cells both in culture and in xenografts. Thus, our findings suggest a tumor suppressor role for APC/C(Cdh1) in melanocytes and that targeting PAX3 may be a strategy for treating melanoma.

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          Most cited references36

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          Cubism and the cell cycle: the many faces of the APC/C.

          One does not often look to analytic cubism for insights into the control of the cell cycle, but Pablo Picasso beautifully encapsulated the fundamentals when he said that "every act of creation is, first of all, an act of destruction". The rapid destruction of specific cell cycle regulators at just the right moment in the cell cycle ensures that daughter cells receive an equal and identical set of chromosomes from their mother and that DNA replication always follows mitosis. Remarkably, one protein complex is responsible for this surgical precision, the APC/C (anaphase-promoting complex, also known as the cyclosome). The APC/C is tightly regulated by its co-activators and by the spindle assembly checkpoint.
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            Genomic stability and tumour suppression by the APC/C cofactor Cdh1.

            The anaphase promoting complex or cyclosome (APC/C) is a ubiquitin protein ligase that, together with Cdc20 or Cdh1, targets cell-cycle proteins for degradation. APC/C-Cdh1 specifically promotes protein degradation in late mitosis and G1. Mutant embryos lacking Cdh1 die at E9.5-E10.5 due to defects in the endoreduplication of trophoblast cells and placental malfunction. This lethality is prevented when Cdh1 is expressed in the placenta. Cdh1-deficient cells proliferate inefficiently and accumulate numeric and structural chromosomal aberrations, indicating that Cdh1 contributes to the maintenance of genomic stability. Cdh1 heterozygous animals show increased susceptibility to spontaneous tumours, suggesting that Cdh1 functions as a haploinsufficient tumour suppressor. These heterozygous mice also show several defects in behaviour associated with increased proliferation of stem cells in the nervous system. These results indicate that Cdh1 is required for preventing unscheduled proliferation of specific progenitor cells and protecting mammalian cells from genomic instability.
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              Spatiotemporal regulation of the anaphase-promoting complex in mitosis.

              The appropriate timing of events that lead to chromosome segregation during mitosis and cytokinesis is essential to prevent aneuploidy, and defects in these processes can contribute to tumorigenesis. Key mitotic regulators are controlled through ubiquitylation and proteasome-mediated degradation. The APC/C (anaphase-promoting complex; also known as the cyclosome) is an E3 ubiquitin ligase that has a crucial function in the regulation of the mitotic cell cycle, particularly at the onset of anaphase and during mitotic exit. Co-activator proteins, inhibitor proteins, protein kinases and phosphatases interact with the APC/C to temporally and spatially control its activity and thus ensure accurate timing of mitotic events.
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                Author and article information

                Journal
                Sci Signal
                Science signaling
                American Association for the Advancement of Science (AAAS)
                1937-9145
                1945-0877
                Sep 01 2015
                : 8
                : 392
                Affiliations
                [1 ] Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
                [2 ] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
                [3 ] Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China.
                [4 ] Molecular Cell Sciences Research Centre, Canadian Cancer Society Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
                [5 ] Department of Molecular and Cell Biology, The University of Texas at Dallas, Dallas, TX 75080, USA.
                [6 ] Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35233, USA.
                [7 ] Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
                [8 ] Department of Developmental, Molecular and Chemical Biology, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
                [9 ] Cancer Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
                [10 ] Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA.
                [11 ] Ludwig Institute for Cancer Research, University of Oxford, Headington, Oxford OX3 7DQ, UK.
                [12 ] Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China. yjwang88@hotmail.com wwei@bidmc.harvard.edu rutaocui@bu.edu.
                [13 ] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. yjwang88@hotmail.com wwei@bidmc.harvard.edu rutaocui@bu.edu.
                [14 ] Department of Pharmacology and Experimental Therapeutics, Boston University Cancer Center, Boston University School of Medicine, Boston, MA 02118, USA. Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 20032, P. R. China. yjwang88@hotmail.com wwei@bidmc.harvard.edu rutaocui@bu.edu.
                Article
                8/392/ra87
                10.1126/scisignal.aab1995
                26329581
                cb04085c-7e01-4e6e-8256-0fc8795f2002
                History

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