Editors' ChoiceDevelopment

Geminin Links Homeobox Domain Proteins to the Cell Cycle

Science's STKE  24 Feb 2004:
Vol. 2004, Issue 221, pp. tw71-TW71
DOI: 10.1126/stke.2212004TW71

Homeobox proteins play an essential role in pattern formation in development. Two groups report an antagonistic interaction between homeobox domain-containing proteins and the cell cycle regulator geminin. Geminin inhibits proliferation by binding to Cdt1, a protein required for the formation of prereplicative complexes needed for DNA replication. Del Bene et al. identified Xenopus geminin as an interacting partner of the homeobox domain-containing transcription factor Six3 in a yeast two-hybrid assay. Geminin binding to Six3 prevented Six3-dependent reporter gene activity but did not inhibit Six3 DNA binding. Six3 competed with Cdt1 for geminin binding, which may make Cdt1 available to participate in DNA replication and so allow cell proliferation. This activity appeared to be independent of the transcriptional regulatory activity of Six3. Various genetic assays confirmed the mutually antagonistic activities of Six3 for geminin's cell cycle suppression activity and geminin for Six3's proliferation activity. Luo et al. identified the Polycomb complex protein Scmh1 and various members of the Hox transcription factor family as partners of geminin in a yeast two-hybrid assay. Cultured cells exhibited colocalization of Polycomb complex proteins and geminin that was dependent on the phase of the cell cycle, with mitotic cells showing colocalization. Geminin also bound directly to DNA containing Hox regulatory elements and to the Hox proteins, which prevented their binding to DNA. Geminin inhibited Hox-stimulated reporter gene expression. Hox proteins also interact with Cdt1, and Hox and geminin competed for binding to Cdt1. These two papers link pathways controlling embryonic cell proliferation and pattern formation through geminin and suggest that not all transcription factor functions arise from regulation of gene expression (see Li and Rosenfeld for discussion).

F. Del Bene, K. Tessmar-Raible, J. Wittbrodt, Direct interaction of geminin and Six3 in eye development. Nature 427, 745-749 (2004). [Online Journal]

L. Luo, X. Yang, Y. Takihara, H. Knoetgen, M. Kessel, The cell-cycle regulator geminin inhibits Hox function through direct and polycomb-mediated interactions. Nature 427, 749-753 (2004). [Online Journal]

X. Li, M. G. Rosenfeld, Origins of licensing control. Nature 427, 687-688 (2004). [Online Journal]