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E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1

Nature Cell Biology volume 4, pages 358–366 (2002)Cite this article

Abstract

Emi1 promotes mitotic entry in Xenopus laevis embryos by inhibiting the APCCdc20 ubiquitination complex to allow accumulation of cyclin B. We show here that human Emi1 (hEmi1) functions to promote cyclin A accumulation and S phase entry in somatic cells by inhibiting the APCCdh1 complex. At the G1–S transition, hEmi1 is transcriptionally induced by the E2F transcription factor, much like cyclin A. hEmi1 overexpression accelerates S phase entry and can override a G1 block caused by overexpression of Cdh1 or the E2F-inhibitor p105 retinoblastoma protein (pRb). Depleting cells of hEmi1 through RNA interference prevents accumulation of cyclin A and inhibits S phase entry. These data suggest that E2F can activate both transcription of cyclin A and the hEmi1-dependent stabilization of APCCdh1 targets, such as cyclin A, to promote S phase entry.

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Figure 1: hEmi1 is a functional homologue of xEmi1.
Figure 2: hEmi1 accumulates at the G1–S transition and is destroyed in early mitosis.
Figure 3: hEmi1 accumulates at the G1–S transition in an E2F-dependent manner.
Figure 4: hEmi1 associates with Cdh1 and inhibits the ubiquitination activity of APCCdh1 in vitro.
Figure 5: hEmi1 overcomes a Cdh1-induced G1 block and prevents destruction of APCCdh1 substrates in vivo.
Figure 6: hEmi1 promotes S phase entry.
Figure 7: Cyclin A accumulation requires hEmi1.

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Acknowledgements

The authors would like to thank T. Wang, J. Peters, T. Hunt, M. Pagano, L. Furstenthal, A. Eldridge, A. Salic, K. Helin, and Clontech for providing important reagents, C. Crumpton for flow cytometric sorting and analysis, A. Bogale for assistance in cell culture, C. Lukas for microinjection experiments, A. Eldridge for critical reading of the manuscript, J. Chao for the TFSEARCH referral, and K. Helin, F. Sprenger, and T. Tuschl for communicating unpublished results. This research is supported by a Cancer Biology Training Grant CA09302 and a Howard Hughes Medical Institute Predoctoral Fellowship to J.Y.H., a National Institute of General Medical Sciences Medical Scientist Training Grant GM07365 to J.D.R.R., the Danish Cancer Society and the Danish Medical Research Council to C.S.S. and J.L., and National Institutes of Health grants GM54811 and GM60439 to P.K.J.

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Authors and Affiliations

  1. Departments of Pathology, Microbiology & Immunology, and Program in Biophysics, Stanford, 94305, CA, USA

    Jerry Y. Hsu, Julie D.R. Reimann & Peter K. Jackson

  2. Program in Cancer Biology, Stanford University School of Medicine, Stanford, 94305, CA, USA

    Jerry Y. Hsu & Peter K. Jackson

  3. Institute of Cancer Biology, Danish Cancer Society, Copenhagen, DK-2100, Denmark

    Claus S. Sørensen & Jiri Lukas

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Correspondence to Peter K. Jackson.

Supplementary information

Figure S1 Sequence and E2F consensus sites of the hEmi1 promoter.

Figure S2 hEmi1 transcripts are upregulated in various tumors. (PDF 303 kb)

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Hsu, J., Reimann, J., Sørensen, C. et al. E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APCCdh1. Nat Cell Biol 4, 358–366 (2002). https://doi.org/10.1038/ncb785

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