FIAT represses ATF4-mediated transcription to regulate bone mass in transgenic mice

We report the characterization of factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT), a leucine zipper nuclear protein. FIAT interacted with ATF4 to inhibit binding of ATF4 to DNA and block ATF4-mediated transcription of the osteocalcin gene in vitro. Transgenic...

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Bibliographic Details
Published in:The Journal of cell biology 2005-05, Vol.169 (4), p.591-601
Main Authors: Yu, Vionnie W.C, Ambartsoumian, Gourgen, Verlinden, Lieve, Moir, Janet M, Prud'homme, Josée, Gauthier, Claude, Roughley, Peter J, St-Arnaud, René
Format: Article
Language:English
Subjects:
Activating Transcription Factor 4
Alkaline Phosphatase - metabolism
Amino Acid Sequence
Animals
Antibodies
Apoptosis - genetics
Base Sequence
Bone and Bones - cytology
Bone and Bones - metabolism
Bone Density - genetics
Bone formation
Bones
Calcification, Physiologic - genetics
Carrier Proteins - genetics
Carrier Proteins - isolation & purification
Carrier Proteins - metabolism
Cell Proliferation
Cercopithecus aethiops
Co-Repressor Proteins
Collagens
COS Cells
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Down-Regulation - genetics
Gene Expression Regulation, Developmental - genetics
Genes
Genes, Regulator - genetics
Leucine Zippers - genetics
Mice
Mice, Transgenic
Molecular Sequence Data
Nuclear Proteins - genetics
Nuclear Proteins - isolation & purification
Nuclear Proteins - metabolism
Osteoblasts
Osteoblasts - metabolism
Osteocalcin - biosynthesis
Osteocalcin - genetics
Osteoclasts - metabolism
Osteogenesis - genetics
Phenotypes
Repressor Proteins - genetics
Repressor Proteins - isolation & purification
Repressor Proteins - metabolism
Stromal cells
Trans-Activators - genetics
Transgenes
Transgenic animals
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Summary:We report the characterization of factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT), a leucine zipper nuclear protein. FIAT interacted with ATF4 to inhibit binding of ATF4 to DNA and block ATF4-mediated transcription of the osteocalcin gene in vitro. Transgenic mice overexpressing FIAT in osteoblasts also had reduced osteocalcin gene expression and decreased bone mineral density, bone volume, mineralized volume, trabecular thickness, trabecular number, and decreased rigidity of long bones. Mineral homeostasis, osteoclast number and activity, and osteoblast proliferation and apoptosis were unchanged in transgenics. Expression of osteoblastic differentiation markers was largely unaffected and type I collagen synthesis was unchanged. Mineral apposition rate was reduced in transgenic mice, suggesting that the lowered bone mass was due to a decline in osteoblast activity. This cell-autonomous decrease in osteoblast activity was confirmed by measuring reduced alkaline phosphatase activity and mineralization in primary osteoblast cultures. These results show that FIAT regulates bone mass accrual and establish FIAT as a novel transcriptional regulator of osteoblastic function.
ISSN:0021-9525
1540-8140
DOI:10.1083/jcb.200412139