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Characterization of the condensin component Cnap1 and protein kinase Melk as novel E2F target genes down-regulated by

Lieve Verlinden1, Guy Eelen, Ine Beullens

  • 1Laboratorium voor Experimentele Geneeskunde en Endocrinologie, Katholieke Universiteit Leuven, Belgium.

The Journal of Biological Chemistry
|September 8, 2005
PubMed

Insights

1,25-Dihydroxyvitamin D(3) inhibits cell proliferation by down-regulating E2F target genes, including Cnap1 and Melk. This effect relies on pocket proteins p107 and p130, impacting cell cycle progression in osteoblasts and other cell types.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) exhibits potent antiproliferative effects.
  • This action is associated with a hampered G(1)/S cell cycle transition.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the antiproliferative effects of 1,25(OH)(2)D(3) in osteoblasts.
  • To identify novel target genes regulated by 1,25(OH)(2)D(3) and the transcription factor E2F.

Main Methods:

  • Gene expression profiling using cDNA microarrays in MC3T3-E1 mouse osteoblasts.
  • Bioinformatic analysis to identify down-regulated genes and E2F binding sites.
  • Transfection studies and site-directed mutagenesis to validate E2F target genes.

Main Results:

  • 1,25(OH)(2)D(3) strongly down-regulated genes involved in cell cycle regulation, DNA replication, and mitosis.
  • Two novel E2F target genes, Cnap1 and Melk, were identified and validated.
  • Down-regulation of Cnap1 and Melk by 1,25(OH)(2)D(3) was observed in multiple cell types.

Conclusions:

  • 1,25(OH)(2)D(3) represses novel E2F target genes Cnap1 and Melk, contributing to its antiproliferative effects.
  • The antiproliferative action and gene repression by 1,25(OH)(2)D(3) are dependent on pocket proteins p107 and p130, but not pRb.

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