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J. Biol. Chem., Vol. 280, Issue 45, 37319-37330, November 11, 2005

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Characterization of the Condensin Component Cnap1 and Protein Kinase Melk as Novel E2F Target Genes Down-regulated by 1,25-Dihydroxyvitamin D₃^*

Lieve Verlinden1, Guy Eelen1, Ine Beullens, Mark Van Camp, Paul Van Hummelen, Kristof Engelen¶, Ruth Van Hellemont¶, Kathleen Marchal¶, Bart De Moor¶, Floris Foijer||, Hein Te Riele||, Monique Beullens**, Mathieu Bollen**, Chantal Mathieu, Roger Bouillon2, and Annemieke Verstuyf

From the Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, 3000 Leuven, Belgium, MicroArray Facility, Vlaams Interuniversitair Instituut voor Biotechnologie (VIB), 3000 Leuven, Belgium, ^¶ESAT-SCD, Katholieke Universiteit Leuven, 3000 Leuven, Belgium, ^**Afdeling Biochemie, Katholieke Universiteit Leuven, Leuven, Belgium, and ^||The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) has potent antiproliferative effects characterized by a hampered G₁/S transition. cDNA microarrays were used to monitor expression of 21,492 genes in MC3T3-E1 mouse osteoblasts at 1, 6, 12, 24, and 36 h after treatment with 1,25(OH)₂D₃. Statistical analysis revealed a cluster of genes that were strongly down-regulated by 1,25(OH)₂D₃ and which not only function in cell cycle regulation and DNA replication but also mediate checkpoint control, DNA repair, chromosome modifications, and mitosis. Because many of these genes were shown earlier to be regulated by the transcriptional repressor E2F4, the intergenic regions of these 1,25(OH)₂D₃-down-regulated genes were searched for the presence of E2F binding sites. This led to the characterization of two novel E2F target genes, chromosome condensation-related SMC-associated protein 1 (Cnap1) and maternal embryonic leucine zipper kinase (Melk). Transfection studies and site-directed mutagenesis confirmed Cnap1 and Melk to be bona fide E2F targets. Repression of Cnap1 and Melk by 1,25(OH)₂D₃ was confirmed not only in MC3T3-E1 cells but also in several other bone-unrelated cell types. This down-regulation as well as the antiproliferative effect of 1,25(OH)₂D₃ depended on the pocket proteins p107 and p130 because 1,25(OH)₂D₃ failed to repress these E2F target genes and lost its antiproliferative action in p107^–/–;p130^–/– cells but not in pRb^–/– cells.

Received for publication, April 1, 2005 , and in revised form, July 27, 2005.

^* This work was supported by Fund for Scientific Research Grants FWO-G.0508.05 and FWO-G.0150.02). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Post-doctoral fellows of the Fund for Scientific Research and equal contributors to this work.

² To whom correspondence should be addressed. Tel.: 32-16-345970; Fax: 32-16-345934; E-mail: Roger.Bouillon{at}med.kuleuven.be.

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