Parathyroid hormone-induced E4BP4/NFIL3 down-regulates transcription in osteoblasts.
Parathyroid hormone (PTH), a major regulator of bone metabolism, activates the PTHR1 receptor on the osteoblast plasma membrane to initiate signaling and induce transcription of primary response genes. Subsequently, primary genes with transcriptional activity regulate expression of downstream PTH targets. We have identified the adenovirus E4 promoter-binding protein/nuclear factor regulated by IL-3 (E4bp4) as a PTH-induced primary gene in osteoblasts. E4BP4 is a basic leucine zipper (bZIP) transcription factor that represses or activates transcription in non-osteoblastic cells. We report here that PTH rapidly and transiently induced E4bp4 mRNA in osteoblastic cells and that this induction did not require protein synthesis. PTH also induced E4BP4 protein synthesis and E4BP4 binding to a consensus but not to a mutant E4BP4 response element (EBPRE). E4BP4 overexpression inhibited an EBPRE-containing promoter-reporter construct, whereas PTH treatment attenuated activity of the same construct in primary mouse osteoblasts. Finally, E4BP4 overexpression inhibited PTH-induced activity of a cyclooxygenase-2 promoter-reporter construct. Our data suggest a role for E4BP4 in attenuation of PTH target gene transcription in osteoblasts.
Division of Diagnostic and Surgical Sciences, UCLA School of Dentistry, Los Angeles, California 90095-1668, USA.
Ibrahim C
IC
Ozkurt
Sotirios
S
Tetradis
D016475:3T3 Cells; D000818:Animals; D001483:Base Sequence; D050976:Basic-Leucine Zipper Transcription Factors; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics*; D015536:Down-Regulation / Q000187:drug effects; D051790:G-Box Binding Factors; D017930:Genes, Reporter / Q000187:drug effects; D016350:Leucine Zippers / Q000235:genetics; D008156:Luciferases / Q000235:genetics; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012886:Skull / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics*; D014158:Transcription, Genetic / Q000187:drug effects
D050976:Basic-Leucine Zipper Transcription Factors; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D051790:G-Box Binding Factors; C497440:NFIL3 protein, human; C497441:Nfil3 protein, mouse; D009687:Nuclear Proteins; D010281:Parathyroid Hormone; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014157:Transcription Factors; D003513:Cycloheximide; D008156:Luciferases