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Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E

Nature Genetics volume 23, pages 245–248 (1999)Cite this article

Abstract

The sequential timing of cell-cycle transitions is primarily governed by the availability and activity of key cell-cycle proteins1. Recent studies in yeast have identified a class of ubiquitin ligases (E3 enzymes) called SCF complexes, which regulate the abundance of proteins that promote2,3,4 and inhibit4,5,6 cell-cycle progression at the G1-S phase transition. SCF complexes consist of three invariable components, Skp1, Cul-1 (Cdc53 in yeast) and Rbx1, and a variable F-box protein that recruits a specific cellular protein to the ubquitin pathway for degradation2,3,5,7,8,9,10,11,12,13. To study the role of Cul-1 in mammalian development and cell-cycle regulation, we generated mice deficient for Cul1 and analysed null embryos and heterozygous cell lines. We show that Cul1 is required for early mouse development and that Cul1 mutants fail to regulate the abundance of the G1 cyclin, cyclin E (encoded by Ccne), during embryogenesis.

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Figure 1: Targeting of the Cul1 genomic locus.
Figure 2: Early embryonic lethality of Cul1 mutant embryos.
Figure 3: Continued proliferation and increased cell death/p53 protein in Cul1 mutant embryos.
Figure 4: Cul-1 limits cyclin E levels in mouse embryos.

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Acknowledgements

We thank the UCSD Cancer Center Histology Core (N. Varki and M. Lawrence) for paraffin embedding and sectioning; A. Lewak, M. Poloni and W. McNulty for technical assistance; J.Y.J. Wang, J. Roberts, R. Hampton, N. Bays, R. Gardner, S. Cronin, A. McElroy, L. Fortunato, C. Johns, G. Bain, P. O'Farrell, J.-K. Heriche, E. Bier, D. Ang, J., N. and A. Dealy, and M. Moreno for advice and assistance; and M. Tyers, J. Cross and Y. Wang for exemplary collegiality.

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Authors and Affiliations

  1. Department of Biology, University of California, San Diego, 9500 Gilman Dr., La Jolla, 92093-0366, California, USA

    Marian J. Dealy, Khanh V.T. Nguyen, Jessica Lo & Randall S. Johnson

  2. Friedrich Miescher Insitut, Maulbeerstrasse 66, Basel, CH-4058, Switzerland

    Matthias Gstaiger & Wilhelm Krek

  3. Department of Surgery, UCSF Cancer Center, University of California, San Francisco, San Francisco, 94143-0808, California, USA

    David Elson & Jeffrey Arbeit

  4. Department of Cellular Biology, University of Georgia, Athens, 30602-2607, Georgia, USA

    Edward T. Kipreos

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  1. Marian J. Dealy
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Correspondence to Randall S. Johnson.

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Dealy, M., Nguyen, K., Lo, J. et al. Loss of Cul1 results in early embryonic lethality and dysregulation of cyclin E. Nat Genet 23, 245–248 (1999). https://doi.org/10.1038/13886

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