Two nuclear signalling pathways for vitamin D.
The dihydroxylated form of vitamin D3 (1,25-dihydroxy-D3)mediates a biological response by binding to intracellular receptors which belong to the steroid receptor superfamily. These receptors act as ligand-dependent transcription factors that bind to specific DNA sequences (reviewed in refs 6-9). We have identified two classes of vitamin D response elements that are activated either by the vitamin D receptor (VDR) alone or by heterodimers of VDR and the retinoid-X receptor-alpha (RXR-alpha). The motif GGGTGA arranged as a direct repeat with a spacing of six nucleotides or as a palindrome without spacing, or as an inverted palindrome with a 12-nucleotide spacing, confers vitamin D inducibility mediated by VDR alone. A second class of response elements, composed of directly repeated pairs of motifs (GGTCCA, AGGTCA, or GGGTGA) spaced by three nucleotides, is synergistically activated by RXR and VDR, but only in the presence of both ligands. Thus, the RXR ligand and the nature of the response element determine whether a nuclear receptor is co-regulated by RXR.
Carlberg
C
C
Department of Pharma Research New Technologies, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Bendik
I
I
Wyss
A
A
Meier
E
E
Sturzenbecker
L J
LJ
Grippo
J F
JF
Hunziker
W
W
D001483:Base Sequence; D001665:Binding Sites; D001943:Breast Neoplasms; D002117:Calcitriol / Q000378:metabolism; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D015675:Osteocalcin / Q000235:genetics; D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface / Q000378:metabolism*; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid / Q000378:metabolism*; D012091:Repetitive Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D015398:Signal Transduction; D014157:Transcription Factors; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014807:Vitamin D / Q000494:pharmacology*
D018167:Receptors, Calcitriol; D011956:Receptors, Cell Surface; D018168:Receptors, Retinoic Acid; D011987:Receptors, Steroid; D047488:Retinoid X Receptors; D014157:Transcription Factors; D015675:Osteocalcin; D014807:Vitamin D; D014212:Tretinoin; D004247:DNA; D002117:Calcitriol