Placenta , Volume 24, Issue 10 , November 2003, Pages 941-950
L. Schäffer (a), A. Scheid (b), P. Spielmann (c), C. Breymann (a), R. Zimmermann (a), M. Meuli (b), M. Gassmann (d), H. H. Marti (c) and R. H. Wenger (e)
(a) Department of Obstetrics and Perinatal Physiology, University Hospital Zürich, Zürich, Switzerland
(b) Department of Surgery, University Children's Hospital of Zürich, CH-8032, Zürich, Switzerland
(c) Institute of Physiology, University of Zürich, CH-8057, Zürich, Switzerland
(d) Institute of Veterinary Physiology, University of Zürich, CH-8057, Zürich, Switzerland
(e) Carl-Ludwig-Institute of Physiology, University of Leipzig, D-04103, Leipzig, Germany
Received 20 March 2003; revised 17 June 2003; accepted 17 June 2003; Available online 2 August 2003.
The transforming growth factor-3 (TGF-3) is involved in oxygen-dependent differentiation processes during placental development and pregnancy disorders. However, the importance of oxgen partial pressure for the regulation of TGF-3 expression is presently unclear. We and others presented preliminary evidence that the hypoxia-inducible factor-1 (HIF-1) confers TGF-3 transcription but it was unknown whether this occurred directly or indirectly. To analyze how HIF-1 regulates TGF-3 gene transcription, we cloned and sequenced the mouse TGF-3 promoter region. Multiple putative HIF-1 binding sites (HBSs) were identified, many of which co-localized with two G+C rich CpG islands 5¢ to the TGF-3 transcription start site. A 6.8 kb fragment of the TGF-3 promoter induced reporter gene expression under hypoxic conditions or when treated with an iron chelator known to stabilize and activate the HIF-1 subunit. Deletion of a 2.4 kb fragment upstream of the distal CpG island abolished inducibility of reporter gene expression. Two HBSs (HBS1 and HBS6) that bound the HIF-1 protein could be identified within this 2.4 kb fragment. These results suggest that TGF-3 gene expression is directly regulated by HIF-1.
Author Keywords: CpG island; Oxygen; Placenta; Transcriptional regulation; Trophoblast; Vasculature
Corresponding author. To whom correspondence should be addressed. Tel.: +49-(0)341-97-15567; Fax: +49-(0)341-97-15509