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Regulation of multiple insulin-like growth factor binding protein genes by 1alpha,25-dihydroxyvitamin D3

Merja Matilainen1, Marjo Malinen, Katri Saavalainen

  • 1Department of Biochemistry, University of Kuopio, P.O. box 1627, IN-70211 Kuopio, Finland.

Nucleic Acids Research
|September 28, 2005
PubMed

Insights

Insulin-like growth factor binding proteins (IGFBPs) 1, 3, and 5 are key targets of vitamin D (1alpha,25(OH)2D3) in cancer cells. Multiple vitamin D response elements (VDREs) control these IGFBP genes, influencing cell proliferation.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Cancer Research

Background:

  • Insulin-like growth factor binding proteins (IGFBPs) mediate vitamin D's effects on cell proliferation.
  • The role of IGFBPs in mediating 1alpha,25-dihydroxyvitamin D3 [1alpha,25(OH)2D3] actions is context-dependent, with potential anti-proliferative or mitogenic effects.
  • Understanding IGFBP gene regulation by 1alpha,25(OH)2D3 is crucial for cancer therapy.

Purpose of the Study:

  • To identify primary 1alpha,25(OH)2D3 target genes among the six human IGFBP genes in prostate and bone cancer cells.
  • To locate and functionally characterize vitamin D response elements (VDREs) regulating IGFBP gene expression.
  • To elucidate the mechanism of 1alpha,25(OH)2D3-mediated regulation of IGFBP genes.

Main Methods:

  • Expression profiling of all six human IGFBP genes in prostate and bone cancer cells.
  • In silico screening for VDREs in the genomic regions of IGFBP genes.
  • In vitro gelshift assays, reporter gene assays, and chromatin immunoprecipitation (ChIP) assays to validate VDRE function and VDR binding.

Main Results:

  • IGFBP1, IGFBP3, and IGFBP5 were identified as primary 1alpha,25(OH)2D3 target genes.
  • Fifteen candidate VDREs were identified, with 10 found to be functional.
  • ChIP assays confirmed the time-dependent association of VDREs with the vitamin D receptor (VDR), retinoid X receptor (RXR), and other transcriptional machinery components.
  • Multiple VDREs, some located distantly, regulate IGFBP1, IGFBP3, and IGFBP5 expression.

Conclusions:

  • IGFBP1, IGFBP3, and IGFBP5 are direct transcriptional targets of 1alpha,25(OH)2D3.
  • Each of these genes is regulated by multiple functional VDREs in intact cells.
  • This provides a deeper understanding of vitamin D's mechanism of action in cancer cells via IGFBP regulation.

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