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Functional characterization of heterogeneous nuclear ribonuclear protein C1/C2 in vitamin D resistance: a novel

Hong Chen1, Martin Hewison, John S Adams

  • 1Division of Endocrinology, Diabetes and Metabolism, Burns and Allen Research Institute, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048, USA.

The Journal of Biological Chemistry
|October 31, 2006
PubMed

Insights

Hereditary vitamin D-resistant rickets can be caused by overexpression of hnRNP C1/C2, a protein that competes with the vitamin D receptor (VDR) for DNA binding. This discovery reveals a new mechanism for vitamin D resistance.

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Genetics

Background:

  • Hereditary vitamin D-resistant rickets (HVDRR) is typically caused by mutations in the vitamin D receptor (VDR).
  • A rare form of HVDRR presents with normal VDR function, suggesting alternative molecular mechanisms.

Purpose of the Study:

  • To identify and characterize the protein responsible for vitamin D resistance in a patient with normal VDR function.
  • To elucidate the molecular mechanism by which this protein causes hormone resistance.

Main Methods:

  • Purification, molecular cloning, and expression of the identified protein.
  • Overexpression studies in vitamin D-responsive cells.
  • Small interfering RNA (siRNA) knockdown experiments.
  • Chromatin immunoprecipitation (ChIP) assays.

Main Results:

  • The protein responsible was identified as heterogeneous nuclear ribonucleoprotein (hnRNP) C1/C2, termed REBiP.
  • Overexpression of hnRNP C1/C2 inhibited VDR-mediated transactivation, while siRNA knockdown enhanced it.
  • ChIP assays revealed that hnRNP C1/C2 competitively binds to the vitamin D response element (VDRE), displacing the VDR.

Conclusions:

  • hnRNP C1/C2 acts as a competitive binding protein (REBiP) that interferes with VDR function.
  • This mechanism of REBiP competition explains vitamin D resistance in the absence of VDR mutations.
  • hnRNP C1/C2 plays a critical role in regulating the temporal dynamics of VDR binding to the VDRE.

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