Postproliferative transcription of the rat osteocalcin gene is reflected by vitamin D-responsive developmental modifications in protein-DNA interactions at basal and enhancer promoter elements
Department of Cell Biology; Department of Medicine, Division of Diabetes
Animals; Base Sequence; Cell Division; Cells, Cultured; DNA; DNA-Binding Proteins; Dexamethasone; *Enhancer Elements (Genetics); Humans; Molecular Sequence Data; Nuclear Proteins; Oligodeoxyribonucleotides; Osteoblasts; Osteocalcin; Phenotype; *Promoter Regions (Genetics); Proto-Oncogene Proteins c-jun; Rats; Receptors, Calcitriol; Receptors, Steroid; TATA Box; *Transcription, Genetic; Vitamin D
Life Sciences | Medicine and Health Sciences
In the osteocalcin (OC) gene promoter, both independent positive and negative regulatory elements, as well as others with contiguous [TATA/glucocorticoid-responsive elements (GRE)] or overlapping [TATA/GRE, vitamin D-responsive enhancer elements (VDRE)/AP-1, and OC box/AP-1] domains, are sites for modifications in protein-DNA interactions. In the present studies, we have examined nuclear protein extracts from fetal rat calvarial cells that undergo a developmental sequence of bone cell differentiation. Our results demonstrate modifications in protein-DNA interactions that relate to the developmental stages of the osteoblast and support developmental regulation of OC gene transcription. Basal expression of the OC gene is associated with sequence-specific protein-DNA interactions at the OC box, VDRE, and TATA/GRE box. Distinct differences are observed in proliferating osteoblasts, where the OC gene is not transcribed compared to postproliferative, differentiated osteoblasts that transcribe the OC gene. Furthermore, the protein-DNA complexes that reflect hormonal control are also developmentally regulated, mediating both the transcriptionally active and repressed states of the OC gene. For example, in proliferating osteoblasts, a vitamin D receptor-antibody-sensitive complex is formed that is different from the DNA binding complex induced by vitamin D postproliferatively when the OC gene is transcribed. Mutational analysis of the steroid hormone binding domain and the overlapping AP-1 site at the VDRE supports mutually exclusive occupancy by Fos-Jun heterodimers and vitamin D receptor. Such protein-DNA interactions at the VDRE are consistent with repression of competency for vitamin D-mediated transcriptional enhancement in proliferating osteoblasts expressing high levels of Fos and Jun.
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Citation: Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1503-7.
Proceedings of the National Academy of Sciences of the United States of America
Owen, T. A.; Bortell, Rita; Shalhoub, Victoria; Heinrichs, A; Stein, Janet L.; Stein, Gary S.; and Lian, Jane B., "Postproliferative transcription of the rat osteocalcin gene is reflected by vitamin D-responsive developmental modifications in protein-DNA interactions at basal and enhancer promoter elements" (1993). Open Access Articles. 1817.