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Genomic stability and tumour suppression by the APC/C cofactor Cdh1

Abstract

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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Figure 1: Generation of Cdh1-deficient mice.
Figure 2: Placental abnormalities in Cdh1-deficient embryos.
Figure 3: Cell proliferation in Cdh1-deficient embryos.
Figure 4: Serum stimulation and DNA replication complexes in Cdh1 mutant cells.
Figure 5: Mitotic progression and exit in Cdh1-deficient cells.
Figure 6: Genomic defects in Cdh1-deficient cells.
Figure 7: Decreased survival and increased susceptibility to tumour development in Cdh1 mutant mice.
Figure 8: Brain abnormalities and altered behaviour in Fzr1+/− mice.

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Acknowledgements

We thank Gardenia Fresneda and Manuel Eguren for help with carcinogenic assays and molecular analysis; and Sheila Rueda and Blanca Velasco for their valuable help in the management of the mouse colony. We also thank Sagrario Ortega and the CNIO Transgenic Unit for their expertise in ES cell manipulations, members of the CNIO Comparative Pathology Unit for histological and pathological processing and the CNIO Cytogenetics Unit for their help with karyotype analysis. I.G.H. is supported by a Ramón y Cajal contract (Ministerio de Educación y Ciencia). E.M. is supported by an FIS fellowship (Ministerio de Sanidad). This work was supported by grants from the Association pour la Recherche contre le Cancer and the Région Aquitaine (to P.D.), Ministerio de Educación y Ciencia (SAF2004-05611 to I.G.H.; BFU2004-04886 to J.M.; BFU2005-03195 and GEN2003-20243-C08-05 to S.M.; and SAF2006-05186 to M.M.), the Consolider-Ingenio 2010 Programme (CSD2007-00015 to J.M. and S.M.; and CSD2007-00017 to M.M.), Comunidad de Madrid (OncoCycle Programme; S-BIO-0283-2006), Fundación Ramón Areces, and Fundación Médica Mutua Madrileña Automovilística (to M.M.); and Fundación Científica de la Asociación Española contra el Cáncer (to S.M. and M.M.).

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I.G.H and E.M. performed most of experiments and J.M. carried out the analysis of chromatin-bound proteins. P.D. and M.C. performed the histological and pathological analysis of the samples. M.M. and S.M. designed and supervised the study and M.M. wrote the manuscript.

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Correspondence to Sergio Moreno or Marcos Malumbres.

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Supplementary Figures S1, S2, S3, S4, S5, Supplementary Tables S1, S2 and Supplementary Methods (PDF 4416 kb)

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García-Higuera, I., Manchado, E., Dubus, P. et al. Genomic stability and tumour suppression by the APC/C cofactor Cdh1. Nat Cell Biol 10, 802–811 (2008). https://doi.org/10.1038/ncb1742

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