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Blood, Vol. 92 No. 12 (December 15), 1998:
pp. 4677-4690
Cloning of the Promoter Region of Human Endoglin, the Target Gene
for Hereditary Hemorrhagic Telangiectasia Type 1
Carlos Ríus,
Joshua D. Smith,
Nuria Almendro,
Carmen Langa,
Luisa M. Botella,
Douglas A. Marchuk,
Calvin P.H. Vary, and
Carmelo Bernabéu
From the Department of Immunology, Centro de Investigaciones
Biológicas, Consejo Superior de Investigaciones
Científicas (CSIC), Madrid, Spain; the Center for Molecular
Medicine, Maine Medical Center Research Institute, South Portland, ME;
and the Department of Genetics, Duke University Medical Center, Durham,
NC.
Endoglin (CD105) is a cell surface component of the transforming
growth factor- (TGF-) receptor complex highly
expressed by endothelial cells. Mutations in the endoglin gene are
responsible for the hereditary hemorrhagic telangiectasia type 1 (HHT1), also known as Osler-Weber-Rendu syndrome (OMIM 187300). This is
an autosomal dominant vascular disorder probably caused by a
haploinsufficiency mechanism displaying low levels of the normal
protein. To understand the mechanisms underlying the regulated
expression of endoglin, a genomic DNA clone containing 3.3 kb of the
5 -flanking sequence of the human endoglin gene has been isolated. The
5-flanking region of the endoglin gene lacks consensus TATA and CAAT
boxes, but contains two GC-rich regions and consensus motifs for Sp1, ets, GATA, AP-2, NF B, and Mad, as well as TGF--,
glucocorticoid-, vitamin D-, and estrogen-responsive elements. As
determined by primer extension and 5 RACE experiments, a cluster of
transcriptional start sites was found to be located 350 bp upstream
from the translation initiation codon. To analyze the endoglin promoter
activity, the upstream  400/+341 fragment was fused to the
luciferase gene and transient transfections were conducted in several
cell types. This construct displayed a tissue-specific activity in
human and bovine endothelial cells. Analysis of various deletion
constructs showed the existence of a basal promoter region within the
81/+350 fragment as well as major transcriptional regulatory
elements within the 400/141 fragment. Electrophoretic mobility
shift assays demonstrated the specific interaction of a member of the ets family with a consensus motif located at position 68. A promoter construct mutated at this ets sequence showed a much reduced activity as compared with the wild-type construct, supporting the involvement of
this ets motif in the basal activity of the promoter. The endoglin promoter exhibited inducibility in the presence of TGF-1, suggesting possible therapeutic treatments in HHT1 patients, in which the expression level of the normal endoglin allele might not reach the
threshold required for its function. Isolation and characterization of
the human endoglin promoter represents an initial step in elucidating the controlled expression of the endoglin gene.
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