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Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

Oncogene volume 26, pages 3406–3414 (2007)Cite this article

Abstract

The Six1 homeoprotein is an important mediator of normal development, where it is critical for the proliferation of precursor cell populations that ultimately constitute the muscle, kidney and inner ear, among other organs. Interestingly, its overexpression has been observed in numerous cancers, where it contributes to the proliferative and metastatic ability of the cancer cells. Here we show that Six1 not only regulates the cell cycle, but is itself regulated throughout the cell cycle via ubiquitin-mediated proteolysis. The protein is present from the G1/S boundary until mitosis, when it is degraded via the anaphase-promoting complex (APC) with its activating subunit Cdh1. However, unlike most identified APCCdh1 targets, Six1 does not contain functional destruction or KEN box motifs that are necessary for its degradation. Instead, the Six1 protein contains multiple, as yet undefined, sequences within its N- and C-termini responsible for its degradation, including an N-terminal region that binds to Cdh1. Cell cycle regulation of Six1 occurs both transcriptionally and post-translationally via phosphorylation; therefore, this study demonstrates a third and novel mechanism of cell cycle-specific regulation of Six1, underscoring the importance of confining its activity to a defined cell cycle window from the G1/S boundary to early mitosis.

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Acknowledgements

We thank William S Lane at the Harvard Microchemistry and Proteomics Analysis Facility for performing mass spectrometry analysis. We thank Carol Dacwag and Edith Kabingu for technical support. We are grateful to Paul Jedlicka, Andrew Bradford and members of the Ford lab for helpful discussions and critical reading of the manuscript. KLC was funded by a predoctoral fellowship from the National Science Foundation. This work was funded by a grant from the National Cancer Institute to HLF (RO1 CA095277).

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Authors and Affiliations

  1. Program in Molecular Biology, University of Colorado at Denver and Health Sciences Center, Fitzsimons Campus, Aurora, CO, USA

    K L Christensen & H L Ford

  2. Department of Obstetrics and Gynecology, University of Colorado at Denver and Health Sciences Center, Fitzsimons Campus, Aurora, CO, USA

    J D G Brennan, C S Aldridge & H L Ford

  3. Department of Biochemistry and Molecular Genetics, University of Colorado at Denver and Health Sciences Center, Fitzsimons Campus, Aurora, CO, USA

    H L Ford

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  1. K L Christensen
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  2. J D G Brennan
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  4. H L Ford
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Correspondence to H L Ford.

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Christensen, K., Brennan, J., Aldridge, C. et al. Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1. Oncogene 26, 3406–3414 (2007). https://doi.org/10.1038/sj.onc.1210122

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