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The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory

Nature Cell Biology volume 10, pages 1083–1089 (2008)Cite this article

Abstract

The anaphase promoting complex (APC) or cyclosome is a multi-subunit E3 ubiquitin ligase. Cdc20 (fizzy (fzy)) or p55CDC, and Cdh1 (Hct1, srw1 or fizzy-related 1 (fzr1)) encode two adaptor proteins that bring substrates to the APC. Both APC–Cdc20 and APC–Cdh1 have been implicated in the control of mitosis through mediating ubiquitination of mitotic regulators, such as cyclin B1 and securin. However, the importance of Cdh1 function in vivo and whether its function is redundant with that of Cdc20 are unclear. Here we have analysed mice lacking Cdh1. We show that Cdh1 is essential for placental development and that its deficiency causes early lethality. Cdh1-deficient mouse embryonic fibroblasts (MEFs) entered replicative senescence prematurely because of stabilization of Ets2 and subsequent activation of p16Ink4a expression. These results have uncovered an unexpected role of the APC in maintaining replicative lifespan of MEFs. Further, Cdh1 heterozygous mice show defects in late-phase long-term potentiation (L-LTP) in the hippocampus and are deficient in contextual fear-conditioning, suggesting that Cdh1 has a role in learning and memory.

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Figure 1: Absence of Cdh1 causes early lethality in mice.
Figure 2: Analysis of Cdh1gt/gt MEFs.
Figure 3: Cdh1 regulates the expression of p16 by modulating the stability of Ets2.
Figure 4: Ets2 is a potential substrate of APC–Cdh1.
Figure 5: Learning and memory defects in Cdh1 heterozygous mice.

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Acknowledgements

The authors thank Dr. H. Yu (Southwestern Medical Center, University of Texas) for technical help, and the transgenic core of BCM for microinjections. We thank E. Shin for excellent technical support. This work was supported in part by a NIH grant CA116097 (P.Z.) and NIH grants NS034007 and NS047384 (E.K.).

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Authors and Affiliations

  1. Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, 77030, TX, USA

    Min Li, Yong-Hyun Shin, Xingxu Huang, Zhubo Wei & Pumin Zhang

  2. Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, 77030, TX, USA

    Pumin Zhang

  3. Center for Neural Science, New York University, New York, 10003, NY, USA

    Lingfei Hou & Eric Klann

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  1. Min Li
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Contributions

M.L., E.R. and P.Z. planned the experiments; M.L., Y.-H. S. and L.H. performed the experimental work and data analyses; X.H. and Z.W. provided technical help; P.Z. wrote the manuscript.

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Correspondence to Pumin Zhang.

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Li, M., Shin, YH., Hou, L. et al. The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory. Nat Cell Biol 10, 1083–1089 (2008). https://doi.org/10.1038/ncb1768

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