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1,25-Dihydroxyvitamin D3 Receptors: Altered Functional Domains are Associated with Cellular Resistance to Vitamin D3

  • J. W. Pike
  • E. A. Allegretto
  • M. A. Kelly
  • C. A. Donaldson
  • S. L. Marion
  • D. J. Mangelsdorf
  • M. R. Haussler
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 196)

Abstract

1,25-Dihydroxyvitamin D3 receptors are cytosoluble proteins detectable in a variety of tissues responsive to 1,25(OH)2D3. They are DNA binding proteins analogous to other steroid receptors and it is this functional property which is likely involved in the activation of hormone-sensitive genes. Utilizing 1,25(OH)2D3 and DNA binding assays, as well as antireceptor monoclonal antibodies, we have probed the relationship between the 1,25(OH)2D3 receptor binding domains after selective cleavage with trypsin. These studies reveal that the hormone and DNA binding regions are separable, and are consistent with the finding that tissue resistance to 1,25(OH)2D3 is a result of structural defects in these domains. Recently, a primate model, the LLC-MK2 monkey kidney line, has been uncovered which may exemplify a hormone-binding defect. Here, 25hydroxyvitamin D3-24-hydroxylase induction, a 1,25(OH)2D3 bioresponse, requires 100-fold higher concentrations of the hormone for maximal response. Concomitantly, this cell contains a variant receptor form which displays a correspondingly lowered apparent affinity for the hormone despite its seemingly normal DNA binding characteristics. Taken together, these studies suggest that the 1,25(OH)2D3 receptor is a macromolecule with multiple domains each of which may produce modified cellular resistance to 1,25(OH)2D3 if structurally altered.

Keywords

Tissue Resistance Mammalian Receptor Linear Salt Gradient Reactive Sulfhydryl Chick Intestine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • J. W. Pike
    • 1
  • E. A. Allegretto
    • 1
  • M. A. Kelly
    • 1
  • C. A. Donaldson
    • 1
  • S. L. Marion
    • 1
  • D. J. Mangelsdorf
    • 1
  • M. R. Haussler
    • 1
  1. 1.Department of BiochemistryUniversity of Arizona Health Sciences CenterTucsonUSA

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