A regulating element essential for PDGFRA transcription is recognized by neural tube defect-associated PRX homeobox transcription factors.
We have previously shown that deregulated expression of the platelet-derived growth factor alpha-receptor (PDGFRA) can be associated with neural tube defects (NTDs) in both men and mice. In the present study, we have investigated the transcription factors that control the up-regulation of PDGFRA expression during differentiation of early embryonic human cells in culture. In Tera-2 embryonal carcinoma cells, PDGFRA expression is strongly enhanced upon differentiation induced by retinoic acid and cAMP treatment. Here we show that the corresponding increase in promoter activity is controlled by an ATTA-sequence-containing element located near the transcription initiation site, which is bound by a transcriptional complex that includes PBX and PRX homeobox transcription factors. Mutation of the putative binding sites for these transcription factors results in strong impairment of PDGFRA promoter activity in differentiated cells. Since functional inactivation of Prx genes has been associated with NTDs in mice, these data support a model in which improper PDGFRA expression as a result of mutations in or altered binding of its upstream regulators may be causally related to NTDs.
Joosten
Paul H L J
PH
Department of Cell Biology, Faculty of Science, University of Nijmegen, Toernooiveld 1, The Netherlands.
Toepoel
Mascha
M
van Oosterhout
Dirk
D
Afink
Gijs B
GB
van Zoelen
Everardus J J
EJ
D000595:Amino Acid Sequence; D000906:Antibodies / Q000737:chemistry; D001665:Binding Sites; D000242:Cyclic AMP / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D009436:Neural Tube Defects / Q000235:genetics*; D010544:Peroxidases / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D014157:Transcription Factors / Q000032:analysis; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D000906:Antibodies; D018398:Homeodomain Proteins; C090465:PBX2 protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D014212:Tretinoin; D000242:Cyclic AMP; D010544:Peroxidases; C120494:anionic peroxidase; D020796:Receptor, Platelet-Derived Growth Factor alpha