Cloning of a functional vitamin D receptor from the lamprey (Petromyzon marinus), an ancient vertebrate lacking a calcified skeleton and teeth.
The nuclear vitamin D receptor (VDR) mediates the actions of its 1,25-dihydroxyvitamin D(3) ligand to control gene expression in terrestrial vertebrates. Prominent functions of VDR-regulated genes are to promote intestinal absorption of calcium and phosphate for bone mineralization and to potentiate the hair cycle in mammals. We report the cloning of VDR from Petromyzon marinus, an unexpected finding because lampreys lack mineralized tissues and hair. Lamprey VDR (lampVDR) clones were obtained via RT-PCR from larval protospleen tissue and skin and mouth of juveniles. LampVDR expressed in transfected mammalian COS-7 cells bound 1,25-dihydroxyvitamin D(3) with high affinity, and transactivated a reporter gene linked to a vitamin D-responsive element from the human CYP3A4 gene, which encodes a P450 enzyme involved in xenobiotic detoxification. In tests with other vitamin D responsive elements, such as that from the rat osteocalcin gene, lampVDR showed little or no activity. Phylogenetic comparisons with nuclear receptors from other vertebrates revealed that lampVDR is a basal member of the VDR grouping, also closely related to the pregnane X receptors and constitutive androstane receptors. We propose that, in this evolutionarily ancient vertebrate, VDR may function in part, like pregnane X receptors and constitutive androstane receptors, to induce P450 enzymes for xenobiotic detoxification.
Whitfield
G Kerr
GK
Department of Biochemistry and Molecular Biophysics, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA. kerr@medbioc.arizona.edu
Dang
Hope T L
HT
Schluter
Samuel F
SF
Bernstein
Ralph M
RM
Bunag
Tara
T
Manzon
Lori A
LA
Hsieh
Grace
G
Dominguez
Carlos Encinas
CE
Youson
John H
JH
Haussler
Mark R
MR
Marchalonis
John J
JJ
D000367:Age Factors; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002113:Calcification, Physiologic; D002117:Calcitriol / Q000378:metabolism; D002356:Cartilage; D003001:Cloning, Molecular; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D019143:Evolution, Molecular; D015870:Gene Expression; D006801:Humans; D007798:Lampreys / Q000235:genetics* / Q000254:growth & development; D008969:Molecular Sequence Data; D010802:Phylogeny; D017434:Protein Structure, Tertiary; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D014070:Tooth; D014158:Transcription, Genetic; D014714:Vertebrates
D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D002117:Calcitriol