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

Hong Chen, Martin Hewison, John S Adams

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32 Citations (Scopus)


Clinically apparent hereditary vitamin D-resistant rickets (HVDRR) usually results from a loss of function mutation in the vitamin D receptor (VDR). We recently described a human with the classical HVDRR phenotype but normal VDR function. Hormone resistance resulted from constitutive overexpression of heterogeneous nuclear ribonucleoprotein (hnRNP) that competed with a normally functioning VDR-retinoid X receptor (RXR) dimer for binding to the vitamin D response element (VDRE). Here we describe the purification, molecular cloning, and expression of this vitamin D resistance-causing, competitive response element-binding protein (REBiP) hnRNP C1/C2. When overexpressed in vitamin D-responsive cells, cDNAs for both hnRNPC1 and hnRNPC2 inhibited VDR-VDRE-directed transactivation (28 and 43%, respectively; both p < 0.005). By contrast, transient expression of an hnRNP C1/C2 small interfering RNA increased VDR transactivation by 39% (p < 0.005). Chromatin immunoprecipitation of nucleoproteins bound to the transcriptionally active 1,25-dihydroxy vitamin D-driven CYP24 promoter revealed the presence of REBiP in vitamin D-responsive human cells and indicated that the normal pattern of 1,25-dihydroxy vitamin D-initiated cyclical movement of the VDR on and off the VDRE is legislated by competitive, reciprocal occupancy of the VDRE by hnRNP C1/C2. The temporal and reciprocal pattern of VDR and hnRNPC1/C2 interaction with the VDRE was lost in HVDRR cells overexpressing the hnRNP C1/C2 REBiP. These observations provide further evidence for the functional importance of REBiP as a component of the multiprotein complex involved in the regulation of vitamin D-mediated transcription. In particular, chromatin immunoprecipitation data suggest that, in addition to its RNA-processing functions, hnRNP C1/C2 may be a key determinant of the temporal patterns of VDRE occupancy.

Original languageEnglish
Pages (from-to)39114-20
Number of pages7
JournalJournal of Biological Chemistry
Issue number51
Publication statusPublished - 22 Dec 2006


  • Amino Acid Sequence
  • Animals
  • Chromatin
  • Cloning, Molecular
  • Heterogeneous-Nuclear Ribonucleoprotein Group C
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Calcitriol
  • Rickets
  • Steroid Hydroxylases
  • Transcription, Genetic
  • Vitamin D
  • Vitamin D3 24-Hydroxylase


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