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

Endocrinology. 1999 Jan;140(1):63-70. doi: 10.1210/endo.140.1.6429.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • DNA / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Osteocalcin / genetics*
  • Osteocalcin / metabolism
  • Promoter Regions, Genetic
  • Rats
  • Receptors, Calcitriol / physiology*
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / physiology
  • Retinoid X Receptors
  • Signal Transduction*
  • Transcription Factor AP-1 / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / physiology
  • Transcription, Genetic
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • Viral Proteins / metabolism

Substances

  • Inhibitor of Apoptosis Proteins
  • Receptors, Calcitriol
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Transcription Factor AP-1
  • Transcription Factors
  • Viral Proteins
  • inhibitor of apoptosis, Nucleopolyhedrovirus
  • Osteocalcin
  • DNA