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Distinct conformations of vitamin D receptor/retinoid X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive elements of the osteocalcin and osteopontin genes

Staal, A ; van Wijnen, A J ; Birkenhäger, J C ; Pols, H A ; Prahl, J ; DeLuca, H ; Gaub, M P ; Lian, J B ; Stein, G S ; van Leeuwen, J P ; Stein, J L

Molecular endocrinology (Baltimore, Md.), 1996-11, Vol.10 (11), p.1444-1456 [Periódico revisado por pares]

United States

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Título:
Distinct conformations of vitamin D receptor/retinoid X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive elements of the osteocalcin and osteopontin genes
Autor: Staal, A ; van Wijnen, A J ; Birkenhäger, J C ; Pols, H A ; Prahl, J ; DeLuca, H ; Gaub, M P ; Lian, J B ; Stein, G S ; van Leeuwen, J P ; Stein, J L
Assuntos: Animals ; Antibodies ; Base Sequence ; Binding Sites ; Binding, Competitive ; Humans ; Mice ; Nucleic Acid Conformation ; Osteocalcin - chemistry ; Osteocalcin - genetics ; Osteocalcin - metabolism ; Osteopontin ; Osteosarcoma - genetics ; Osteosarcoma - metabolism ; Osteosarcoma - pathology ; Point Mutation ; Protein Conformation ; Rats ; Receptors, Calcitriol - chemistry ; Receptors, Calcitriol - immunology ; Receptors, Calcitriol - metabolism ; Receptors, Retinoic Acid - chemistry ; Receptors, Retinoic Acid - immunology ; Receptors, Retinoic Acid - metabolism ; Retinoid X Receptors ; Sialoglycoproteins - chemistry ; Sialoglycoproteins - genetics ; Sialoglycoproteins - metabolism ; Steroids - metabolism ; Transcription Factors - chemistry ; Transcription Factors - immunology ; Transcription Factors - metabolism ; Tumor Cells, Cultured ; Vitamin D - metabolism
É parte de: Molecular endocrinology (Baltimore, Md.), 1996-11, Vol.10 (11), p.1444-1456
Notas: ObjectType-Article-2
SourceType-Scholarly Journals-1
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Descrição: The 1 alpha,25-dihydroxyvitamin D3 (VD3)-dependent stimulation of osteocalcin (OC) and osteopontin (OP) gene transcription in bone tissue is mediated by interactions of trans-activating factors with distinct VD3-responsive elements (VDREs). Sequence variation between the OC- and OP-VDRE steroid hormone half-elements provides the potential for recognition by distinct hormone receptor homo- and heterodimers. However, the exact composition of endogenous VD3- induced complexes recognizing the OC- and OP-VDREs in osteoblasts has not been definitively established. To determine the identity of these complexes, we performed gel shift immunoassays with nuclear proteins from ROS 17/ 2.8 osteoblastic cells using a panel of monoclonal antibodies. We show that VD3- inducible complexes interacting with the OC- and OP-VDREs represent two distinct heterodimeric complexes, each composed of the vitamin D receptor (VDR) and the retinoid X receptor-alpha (RXR). The OC- and OP-VDR/RXR alpha heterodimers are immunoreactive with RXR antibodies and several antibodies directed against the ligand-binding domain of the VDR. However, while the OC-VDRE complex is also efficiently recognized by specific monoclonal antibodies contacting epitopes in or near the VDR DNA-binding domain (DBD) (between amino acids 57-164), the OP-VDRE complex is not efficiently recognized by these antibodies. By systematically introducing a series of point-mutations in the OC-VDRE, we find that two internal nucleotides of the proximal OC-VDRE half-site (nucleotide -449 and -448; 5'-AGGACA) determine differences in VDR immunoreactivity. These results are consistent with the well established polarity of RXR heterodimer binding to bipartite hormone response elements, with the VDR recognizing the 3'-half-element. Furthermore, our data suggest that the DBD of the VDR adopts different protein conformations when contacting distinct VDREs. Distinctions between the OC- and OP-VDR/RXR alpha complexes may reflect specialized requirements for VD3 regulation of OC and OP gene expression in response to physiological cues mediating osteoblast differentiation.
Editor: United States
Idioma: Inglês

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Distinct conformations of vitamin D receptor/retinoid X receptor-alpha heterodimers are specified by dinucleotide differences in the vitamin D-responsive elements of the osteocalcin and osteopontin genes

Staal, A ; van Wijnen, A J ; Birkenhäger, J C ; Pols, H A ; Prahl, J ; DeLuca, H ; Gaub, M P ; Lian, J B ; Stein, G S ; van Leeuwen, J P ; Stein, J L

United States

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