The adaptor protein of the anaphase promoting complex Cdh1 is essential in maintaining replicative lifespan and in learning and memory.
The anaphase promoting complex (APC) or cyclosome is a multisubunit 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. Cdhl-deficient mouse embryonic fibroblasts (MEFs) entered replicative senescence prematurely because of stabilization of Ets2 and subsequent activation of p6(Ink4a) 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.
Li
Min
M
Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Shin
Yong-Hyun
YH
Hou
Lingfei
L
Huang
Xingxu
X
Wei
Zhubo
Z
Klann
Eric
E
Zhang
Pumin
P
D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D020964:Embryo Loss / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006579:Heterozygote; D066298:In Vitro Techniques; D008568:Memory / Q000502:physiology*; D051379:Mice; D055550:Protein Stability; D050787:Proto-Oncogene Protein c-ets-2 / Q000378:metabolism; D013379:Substrate Specificity; D043743:Ubiquitin-Protein Ligase Complexes / Q000378:metabolism*
D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C494070:Ets2 protein, mouse; C577585:Fzr1 protein, mouse; D050787:Proto-Oncogene Protein c-ets-2; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome