Regulation of the 1,25-dihydroxyvitamin D3 receptor by 1,25-dihydroxyvitamin D3 in intact human cancer cells.
Human breast cancer cells have been shown to be targets of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]action with specific dose-dependent effects on growth in vitro. These cells possess specific, high affinity receptors for 1,25-(OH)2D3. We have studied the interaction of the vitamin D hormone with its receptor in these intact human target cells. Specific binding of tritium-labeled 1,25-(OH)2D3 by these cells reaches a maximum with 3-9 h depending on hormone concentration; subsequently there is a rapid loss of hormone-binding activity to virtually undetectable levels by 12-24 h. Although the hormone induces its own metabolism in these cells, binding cannot be restored by the addition of fresh hormone. This loss of hormone-binding activity of the receptor, is analogous to the processing of the estrogen receptor in estrogen receptor-positive cells. Two inhibitors of DNA transcription, actinomycin D and cordycepin, delay the onset and slow the processing of receptor if added with the hormone. They are ineffective if added after hormone binding is maximal. Inhibitors of protein synthesis have no protective effect at all and, in fact, these agents inhibit both the attainment of maximum specific binding and the recovery of receptor over the subsequent 24-72 h. These data demonstrate for the first time that the 1,25-(OH)2D3 receptor undergoes regulation in the intact human target cell. This event, which resembles processing of the estrogen receptor and down-regulation of peptide-hormone receptors, likely represents a nuclear mechanism for the control of cellular responsiveness to hormone in the intact cell.
Sher
E
E
Frampton
R J
RJ
Eisman
J A
JA
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002117:Calcitriol / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D003839:Deoxyadenosines / Q000494:pharmacology; D006801:Humans; D011691:Puromycin / Q000494:pharmacology; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors; D014316:Tritium
D003839:Deoxyadenosines; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014316:Tritium; D003609:Dactinomycin; D011691:Puromycin; D003513:Cycloheximide; D002117:Calcitriol