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Mechanisms of nuclear vitamin D receptor resistance in Harvey-ras-transfected cells

Laura M Taber1, Lynn S Adams, Dorothy Teegarden

  • 1Department of Foods and Nutrition, Purdue University, West Lafayette, IN 47907, USA.

The Journal of Nutritional Biochemistry
|October 3, 2008
PubMed

Insights

The Harvey ras gene suppresses vitamin D receptor (VDR) activity by interfering with its DNA binding. Phosphatidylinositol 3-kinase (PI3K) activation is identified as a key pathway mediating this suppression, impacting gene transcription.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Endocrinology

Background:

  • 1,25 dihydroxyvitamin D (1,25(OH)(2)D) is a hormone that regulates gene transcription via the nuclear vitamin D receptor (nVDR).
  • Previous studies indicated that the Harvey ras (H-ras) gene reduces 1,25(OH)(2)D-induced nVDR transcriptional activity in fibroblast cells.

Purpose of the Study:

  • To elucidate the mechanisms by which the H-ras gene impairs nVDR transcriptional activity.
  • To identify specific signaling pathways involved in H-ras-mediated suppression of VDR function.

Main Methods:

  • Utilized C3H10T1/2 fibroblast cells, some transfected with the H-ras gene (ras cells).
  • Assessed nVDR transcriptional activity, RXRalpha protein levels, and nVDR binding to vitamin D response elements (VDREs).
  • Employed inhibitors for extracellular signal-regulated kinase (ERK1/2), 24-hydroxylase, protein kinase C, and phosphatidylinositol 3-kinase (PI3K).

Main Results:

  • H-ras gene induction reduced nVDR transcriptional activity and nVDR binding to VDREs.
  • RXRalpha levels were comparable between ras and parental cells; RXRalpha overexpression did not rescue VDR activity.
  • Inhibition of ERK1/2, 24-hydroxylase, or protein kinase C had no effect, while PI3K inhibition increased nVDR activity in ras cells.

Conclusions:

  • The H-ras gene suppresses 1,25(OH)(2)D-mediated nVDR transcriptional activity.
  • Phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a significant role in mediating H-ras-induced suppression of nVDR function.
  • H-ras interference with VDR transcriptional activity may involve reduced nVDR binding to VDREs, potentially mediated by PI3K.

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