The VCAM-1 gene that encodes the vascular cell adhesion molecule is a target of the Sry-related high mobility group box gene, Sox18.
VCAM-1 (vascular cell adhesion molecule-1) and Sox18 are involved in vascular development. VCAM-1 is an important adhesion molecule that is expressed on endothelial cells and has a critical role in endothelial activation, inflammation, lymphatic pathophysiology, and atherogenesis. The Sry-related high mobility group box factor Sox18 has previously been implicated in endothelial pathologies. Mutations in human and mouse Sox18 leads to hypotrichosis and lymphedema. Furthermore, both Sox18 and VCAM-1 have very similar spatio-temporal patterns of expression, which is suggestive of cross-talk. We use biochemical techniques, cell culture systems, and the ragged opossum (RaOP) mouse model with a naturally occurring mutation in Sox18 to demonstrate that VCAM-1 is an important target of Sox18. Transfection, site-specific mutagenesis, and gel shift analyses demonstrated that Sox18 directly targeted and trans-activated VCAM-1 expression. Importantly, the naturally occurring Sox18 mutant attenuates the expression and activation of VCAM-1 in vitro. Furthermore, in vivo quantitation of VCAM-1 mRNA levels in wild type and RaOP mice demonstrates that RaOP animals show a dramatic and significant reduction in VCAM-1 mRNA expression in lung, skin, and skeletal muscle. Our observation that the VCAM-1 gene is an important target of SOX18 provides the first molecular insights into the vascular abnormalities in the mouse mutant ragged and the human hypotrichosis-lymphedema-telangiectasia disorder.
Hosking
Brett M
BM
Institute for Molecular Bioscience, Queensland Biosciences Precinct, University of Queensland, Brisbane, Queensland 4072, Australia.
Wang
S-C Mary
SC
Downes
Meredith
M
Koopman
Peter
P
Muscat
George E O
GE
D000483:Alleles; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002448:Cell Adhesion; D018929:Cell Culture Techniques; D002460:Cell Line; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005982:Glutathione Transferase / Q000378:metabolism; D006609:High Mobility Group Proteins / Q000235:genetics* / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009893:Opossums; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055760:SOXF Transcription Factors; D013997:Time Factors; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
D018076:DNA, Complementary; D006609:High Mobility Group Proteins; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; C095473:SOX18 protein, human; D055760:SOXF Transcription Factors; C490653:Sox18 protein, mouse; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; D008156:Luciferases; D005982:Glutathione Transferase