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Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1.

Publication ,  Journal Article
Ríus, C; Smith, JD; Almendro, N; Langa, C; Botella, LM; Marchuk, DA; Vary, CP; Bernabéu, C
Published in: Blood
December 15, 1998

Endoglin (CD105) is a cell surface component of the transforming growth factor-beta (TGF-beta) 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, NFkappaB, and Mad, as well as TGF-beta-, 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-beta1, 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.

Duke Scholars

Published In

Blood

ISSN

0006-4971

Publication Date

December 15, 1998

Volume

92

Issue

12

Start / End Page

4677 / 4690

Location

United States

Related Subject Headings

  • Vascular Cell Adhesion Molecule-1
  • Transforming Growth Factor beta
  • Transcription, Genetic
  • Telangiectasia, Hereditary Hemorrhagic
  • Sequence Analysis, DNA
  • Regulatory Sequences, Nucleic Acid
  • Receptors, Cell Surface
  • Promoter Regions, Genetic
  • Organ Specificity
  • Mutagenesis, Site-Directed
 

Citation

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Chicago
ICMJE
MLA
NLM
Ríus, C., Smith, J. D., Almendro, N., Langa, C., Botella, L. M., Marchuk, D. A., … Bernabéu, C. (1998). Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood, 92(12), 4677–4690.
Ríus, C., J. D. Smith, N. Almendro, C. Langa, L. M. Botella, D. A. Marchuk, C. P. Vary, and C. Bernabéu. “Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1.Blood 92, no. 12 (December 15, 1998): 4677–90.
Ríus C, Smith JD, Almendro N, Langa C, Botella LM, Marchuk DA, et al. Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood. 1998 Dec 15;92(12):4677–90.
Ríus C, Smith JD, Almendro N, Langa C, Botella LM, Marchuk DA, Vary CP, Bernabéu C. Cloning of the promoter region of human endoglin, the target gene for hereditary hemorrhagic telangiectasia type 1. Blood. 1998 Dec 15;92(12):4677–4690.

Published In

Blood

ISSN

0006-4971

Publication Date

December 15, 1998

Volume

92

Issue

12

Start / End Page

4677 / 4690

Location

United States

Related Subject Headings

  • Vascular Cell Adhesion Molecule-1
  • Transforming Growth Factor beta
  • Transcription, Genetic
  • Telangiectasia, Hereditary Hemorrhagic
  • Sequence Analysis, DNA
  • Regulatory Sequences, Nucleic Acid
  • Receptors, Cell Surface
  • Promoter Regions, Genetic
  • Organ Specificity
  • Mutagenesis, Site-Directed