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The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions

Abstract

Embryonic development is tightly controlled. The clustered genes of the Hox family of homeobox proteins play an important part in regulating this development and also proliferation. They specify embryonic structures along the body axis, and are associated with normal and malignant cell growth1,2,3,4. The cell-cycle regulator geminin controls replication by binding to the licensing factor Cdt1, and is involved in neural differentiation5,6,7. Here, we show that murine geminin associates transiently with members of the Hox-repressing polycomb complex, with the chromatin of Hox regulatory DNA elements and with Hox proteins. Gain- and loss-of-function experiments in the chick neural tube demonstrate that geminin modulates the anterior boundary of Hoxb9 transcription, which suggests a polycomb-like activity for geminin. The interaction between geminin and Hox proteins prevents Hox proteins from binding to DNA, inhibits Hox-dependent transcriptional activation of reporter and endogenous downstream target genes, and displaces Cdt1 from its complex with geminin. By establishing competitive regulation, geminin functions as a coordinator of developmental and proliferative control.

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Figure 1: Isolation of Hox and Scmh1 as geminin-binding proteins.
Figure 2: Geminin associates with the polycomb complex and Hox regulatory DNA elements in vivo.
Figure 3: Geminin modulates the anterior boundary of endogenous Hoxb9 transcription in the avian neural tube.
Figure 4: The geminin–Hox interaction inhibits DNA binding and competes with Cdt1–geminin complex formation.

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References

  1. Krumlauf, R. Hox genes in vertebrate development. Cell 78, 191–200 (1994)

    Article  CAS  Google Scholar 

  2. Kessel, M. & Gruss, P. Homeotic transformations of murine vertebrae and concomitant alteration of Hox codes induced by retinoic acid. Cell 67, 89–104 (1991)

    Article  CAS  Google Scholar 

  3. Schumacher, A. & Magnuson, T. Murine Polycomb- and trithorax-group genes regulate homeotic pathways and beyond. Trends Genet. 13, 167–170 (1997)

    Article  CAS  Google Scholar 

  4. Abate-Shen, C. Deregulated homeobox gene expression in cancer: cause or consequence? Nature Rev. Cancer 2, 777–785 (2002)

    Article  CAS  Google Scholar 

  5. Wohlschlegel, J. A. et al. Inhibition of eukaryotic DNA replication by Geminin binding to Cdt1. Science 290, 2309–2312 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Tada, S., Li, A., Maiorano, D., Méchali, M. & Blow, J. J. Repression of origin assembly in metaphase depends on inhibition of RLF-B/Cdt1 by Geminin. Nature Cell Biol. 3, 107–113 (2001)

    Article  CAS  Google Scholar 

  7. Kroll, K. L., Salic, A. N., Evans, L. M. & Kirschner, M. W. Geminin, a neuralizing molecule that demarcates the future neural plate at the onset of gastrulation. Development 125, 3247–3258 (1998)

    CAS  Google Scholar 

  8. Bornemann, D., Miller, E. & Simon, J. The Drosophila Polycomb group gene Sex comb on midleg (Scm) encodes a zinc finger protein with similarity to polyhomeotic protein. Development 122, 1621–1630 (1996)

    CAS  PubMed  Google Scholar 

  9. Tomotsune, D. et al. A novel member of murine Polycomb-group proteins, Sex comb on midleg homolog protein, is highly conserved, and interacts with Rae28/Mph1 in vitro. Differentiation 65, 229–239 (1999)

    Article  CAS  Google Scholar 

  10. Takihara, Y. et al. Targeted disruption of the mouse homologue of the Drosophila polyhomeotic gene leads to altered anteroposterior patterning and neural crest defects. Development 124, 3673–3682 (1997)

    CAS  PubMed  Google Scholar 

  11. Akasaka, T. et al. A role of mel-18, a Polycomb group-related vertebrate gene, during the anteroposterior specification of the axial skeleton. Development 122, 1513–1522 (1996)

    CAS  PubMed  Google Scholar 

  12. Kulartz, M. et al. Expression and phosphorylation of the replication regulator protein geminin. Biochem. Biophys. Res. Commun. 305, 412–420 (2003)

    Article  CAS  Google Scholar 

  13. Barna, M. et al. Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev. Cell 3, 499–510 (2002)

    Article  CAS  Google Scholar 

  14. Pekarik, V. et al. Screening for gene function in chicken embryo using RNAi and electroporation. Nature Biotechnol. 21, 93–96 (2003)

    Article  CAS  Google Scholar 

  15. McGarry, T. J. & Kirschner, M. W. Geminin, an inhibitor of DNA replication, is degraded during mitosis. Cell 93, 1043–1053 (1998)

    Article  CAS  Google Scholar 

  16. Del Bene, F., Tessmar-Raible, K. & Wittbrodt, J. Direct interaction of geminin and Six3 in eye development. Nature 427, 745–749 (2004)

    Article  ADS  CAS  Google Scholar 

  17. Care, A. et al. HoxB7 constitutively activates basic fibroblast growth factor in melanomas. Mol. Cell. Biol. 16, 4842–4851 (1996)

    Article  CAS  Google Scholar 

  18. Duboule, D. Vertebrate Hox genes and proliferation: an alternative pathway to homeosis? Curr. Opin. Genet. Dev. 5, 525–528 (1995)

    Article  CAS  Google Scholar 

  19. Tetsu, O. et al. Mel-18 negatively regulates cell cycle progression upon B cell antigen receptor stimulation through a cascade leading to c-myc/cdc25. Immunity 9, 439–448 (1998)

    Article  CAS  Google Scholar 

  20. Krosl, J. et al. Cellular proliferation and transformation induced by HOXB4 and HOXB3 proteins involves cooperation with PBX1. Oncogene 16, 3403–3412 (1998)

    Article  CAS  Google Scholar 

  21. Thorsteinsdottir, U. et al. Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia. Mol. Cell. Biol. 17, 495–505 (1997)

    Article  CAS  Google Scholar 

  22. Wohlschlegel, J. A., Kutok, J. L., Weng, A. P. & Dutta, A. Expression of geminin as a marker of cell proliferation in normal tissues and malignancies. Am. J. Pathol. 161, 267–273 (2002)

    Article  CAS  Google Scholar 

  23. Gabellini, D. et al. Early mitotic degradation of the homeoprotein HOXC10 is potentially linked to cell cycle progression. EMBO J. 22, 3715–3724 (2003)

    Article  CAS  Google Scholar 

  24. Suzuki, M. et al. Involvement of the Polycomb-group gene Ring1B in the specification of the anterior–posterior axis in mice. Development 129, 4171–4183 (2002)

    CAS  PubMed  Google Scholar 

  25. Saurin, A. J. et al. The human Polycomb group complex associates with pericentromeric heterochromatin to form a novel nuclear domain. J. Cell Biol. 142, 887–898 (1998)

    Article  CAS  Google Scholar 

  26. Megason, S. G. & McMahon, A. P. A mitogen gradient of dorsal midline Wnts organizes growth in the CNS. Development 129, 2087–2098 (2002)

    CAS  PubMed  Google Scholar 

  27. Shen, W.-F. et al. AbdB-like Hox proteins stabilize DNA binding by the Meis1 homeodomain proteins. Mol. Cell. Biol. 17, 6448–6458 (1997)

    Article  CAS  Google Scholar 

  28. Semenza, G. L., Wang, G. L. & Kundu, R. DNA binding and transcriptional properties of wild-type and mutant forms of the homeodomain protein Msx2. Biochem. Biophys. Res. Commun. 209, 257–262 (1995)

    Article  CAS  Google Scholar 

  29. Elbashir, S. M., Harborth, J., Weber, K. & Tuschl, T. Analysis of gene function in somatic mammalian cells using small interfering RNAs. Methods 26, 199–213 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank D. Duboule, A. Dutta, C. J. Tabin, S. Potter, R. Maas and H. Koseki for plasmids and antibodies, M. Pitulescu for discussions, J. Wittbrodt for communication and discussion of unpublished results, and P. Gruss and D. Gallwitz for their continuous support. This work was funded by the Max Planck Society and a DFG grant.

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Correspondence to Michael Kessel.

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Supplementary information

Supplementary Figure 1

a, b, Subcellular co-localization of Geminin and Rae28/Mph1 or Mel18. (JPG 63 kb)

Supplementary Figure 2

Geminin inhibits transcriptional activation by Hoxa11 or Hoxb7. (JPG 35 kb)

Supplementary Figure Legends (DOC 28 kb)

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Luo, L., Yang, X., Takihara, Y. et al. The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions. Nature 427, 749–753 (2004). https://doi.org/10.1038/nature02305

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