Chfr is required for tumor suppression and Aurora A regulation

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Abstract

Tumorigenesis is a consequence of loss of tumor suppressors and activation of oncogenes. Expression of the mitotic checkpoint protein Chfr is lost in 20–50% of primary tumors and tumor cell lines. To explore whether downregulation of Chfr contributes directly to tumorigenesis, we generated Chfr knockout mice. Chfr-deficient mice are cancer-prone, develop spontaneous tumors and have increased skin tumor incidence after treatment with dimethylbenz(a)anthracene. Chfr deficiency leads to chromosomal instability in embryonic fibroblasts and regulates the mitotic kinase Aurora A, which is frequently upregulated in a variety of tumors. Chfr physically interacts with Aurora A and ubiquitinates Aurora A both in vitro and in vivo. Collectively, our data suggest that Chfr is a tumor suppressor and ensures chromosomal stability by controlling the expression levels of key mitotic proteins such as Aurora A.

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Figure 1: Targeted disruption of Chfr in mice.
Figure 2: Chfr deficiency increases tumor incidence in mice.
Figure 3: Loss of Chfr leads to chromosome instability.
Figure 4: Chfr negatively regulates expression of Aurora A.
Figure 5: Chfr interacts with Aurora A and ubiquitinates Aurora A both in vitro and in vivo.
Figure 6: Downregulation of Aurora A decreases the aneuploidy observed in Chfr−/− MEFs.

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Acknowledgements

We thank D. Lim, D. Haines, E. Nigg, S. Sen, T. Takahashi, J. Cheng, R. Baer, L. Van Parijs, J. Chien and K. Minn for reagents and help; J. Woods for proofreading the manuscript; and S. Kaufmann and W. Earnshaw for suggestions. This work is supported in part by the Mayo Clinic Cancer Center and the Breast Cancer Research Foundation. J.C. is a recipient of the Department of Defense breast cancer career development award.

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Correspondence to Junjie Chen.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Tumor-free survival of wild-type and Chfr-deficient mice (from 40-80 weeks). (PDF 183 kb)

Supplementary Fig. 2

Spontaneous foci formation in Chfr-/- MEFs. (PDF 216 kb)

Supplementary Fig. 3

Chfr does not ubiquitinate Aurora B in vivo. (PDF 135 kb)

Supplementary Fig. 4

Endogenous Aurora A is ubiquitinated by Chfr. (PDF 382 kb)

Supplementary Table 1

Organs affected by tumors in wild-type and Chfr-deficient mice (40-80 weeks). (PDF 163 kb)

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