Distinct activities of the anaphase-promoting complex/cyclosome (APC/C) in mouse embryonic cells |
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| Authors: | Valerie S Yang Stephanie A Carter Yifan Ng Sarah J Hyland Kiku? Tachibana-Konwalski Rosemary A Fisher Neil J Sebire Michael J Seckl Roger A Pedersen Ronald A Laskey Michael A Gonzalez |
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| Institution: | 1.MRC Cancer Cell Unit; Hutchison-MRC Research Centre; Cambridge, UK;2.Anne McLaren Laboratory for Regenerative Medicine/MRC Centre for Stem Cell Biology and Regenerative Medicine; University of Cambridge; Cambridge, UK;3.IMBA; Institute of Molecular Biotechnology of the Austrian Academy of Sciences; Vienna, Austria;4.Trophoblastic Disease Centre; Department of Medical Oncology; Charing Cross Hospital; London, UK |
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| Abstract: | The first differentiation event in mammalian development gives rise to the blastocyst, consisting of two cell lineages that have also segregated in how the cell cycle is structured. Pluripotent cells of the inner cell mass divide mitotically to retain a diploid DNA content, but the outer trophoblast cells can amplify their genomes more than 500-fold by undergoing multiple rounds of DNA replication, completely bypassing mitosis. Central to this striking divergence in cell cycle control is the E3 ubiquitin-ligase activity of the anaphase-promoting complex or cyclosome (APC/C). Extended suppression of APC/C activity during interphase of mouse pluripotent cells promotes rapid cell cycle progression by allowing stabilization of cyclins, whereas unopposed APC/C activity during S phase of mouse trophoblast cells triggers proteasomal-mediated degradation of geminin and giant cell formation. While differential APC/C activity might govern the atypical cell cycles observed in pre-implantation mouse embryos, geminin is a critical APC/C substrate that: (1) escapes degradation in pluripotent cells to maintain expression of Oct4, Sox2 and Nanog and (2) mediates specification and endoreduplication when targeted for ectopic destruction in trophoblast. Thus, in contrast to trophoblast giant cells that lack geminin, geminin is preserved in both mouse pluripotent cells and non-endoreduplicating human cytotrophoblast cells.Key words: APC/C, geminin, Emi1, cell cycle, pluripotency, trophoblast, endoreduplication, DNA damage |
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