AP-1 and vitamin D receptor (VDR) signaling pathways converge at the rat osteocalcin VDR element: requirement for the internal activating protein-1 site for vitamin D-mediated trans-activation.
Responsiveness of genes to steroid hormones is a complex process involving synergistic and/or antagonistic interactions between specific receptors and other nonreceptor transcription factors. Thus, DNA recognition elements for steroid hormone receptors are often located among binding sites for other trans-acting factors. The hormonal form of vitamin D, 1,25-dihydroxyvitamin D3, stimulates transcription of the tissue-specific osteocalcin (OC) gene in osteoblastic cells. The rat OC vitamin D response element contains an internal acitvating protein-1 (AP-1) site. Here, we report for the first time that this AP-1 site is critical for the transcriptional enhancement of rat osteocalcin gene expression mediated by vitamin D. Precise mutations were introduced either in the steroid half-elements or in the internal AP-1 sequences. One mutation within the internal AP-1 site retained vitamin D receptor/retinoid X receptor binding equivalent to that of the wild-type sequence, but resulted in complete loss of vitamin D inducibility of the OC promoter. These results suggest a functional interaction between the hormone receptor and nuclear oncoproteins at the rat OC vitamin D response element. This cooperation of activities may have important consequences in physiological regulation of osteocalcin transcription during osteoblast differentiation and bone tissue development in vivo.
Aslam
F
F
Department of Cell Biology, University of Massachusetts Medical Center, Worcester 01655, USA.
McCabe
L
L
Frenkel
B
B
van Wijnen
A J
AJ
Stein
G S
GS
Lian
J B
JB
Stein
J L
JL
D000818:Animals; D004247:DNA / Q000378:metabolism; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D015675:Osteocalcin / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D018167:Receptors, Calcitriol / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000502:physiology; D047488:Retinoid X Receptors; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D014764:Viral Proteins / Q000378:metabolism
D051034:Inhibitor of Apoptosis Proteins; D018167:Receptors, Calcitriol; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014764:Viral Proteins; C086430:inhibitor of apoptosis, Nucleopolyhedrovirus; D015675:Osteocalcin; D004247:DNA