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DNA Sequences Downstream from the Vitamin D Response Element of the Rat Osteocalcin Gene Are Required for Ligand-Dependent Transactivation

Endocrine Unit Massachusetts General Hospital Harvard Medical School Boston, Massachusetts 02114

The sequences in the rat osteocalcin gene that lie 3' to the vitamin D response element (VDRE) have been shown to augment transcriptional activation by 1,25-dihydroxyvitamin D₃ [1,25-(OH)₂D₃]. These DNA sequences, however, are unable to bind the VDR or mediate 1,25-(OH)₂D₃ responsiveness independently of the VDRE. To further characterize this region, the functional properties of a series of mutant oligonucleotides were examined in transiently transfected ROS 17/2.8 cells. When these mutant oligonucleotides were expressed upstream of the heterologous herpes simplex virus thymidine kinase promoter, the bases between -420 and -414 of the rat osteocalcin gene were identified as critical for maximal transactivation by 1,25-(OH)₂D₃. Furthermore, mutation of these sequences in the context of the native osteocalcin promoter and enhancer totally abolished the ability of the VDRE to mediate 1,25-(OH)₂D₃ responsiveness. These bases, which are essential for the 1,25-(OH)₂D₃ responsiveness of the rat osteocalcin gene, are also present in a similar position, relative to the VDRE, in the human osteocalcin gene. To explore whether these sequences could enhance transactivation by other inducible transcription factors, they were examined for their ability to synergize with the chick vitellogenin estrogen response element and the rat somatostatin cAMP response element. When placed upstream to the herpes simplex virus thymidine kinase promoter and transfected into ROS 17/2.8 cells, these sequences were able to enhance transcriptional responsiveness to 17ß-estradiol and forskolin, respectively, demonstrating that they also contribute to transactivation by other inducible transcription factors.

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