Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice

Hosking, B, Francois, M, Wilhelm, D, Orsenigo, F, Caprini, A, Svingen, T, Tutt, D, Davidson, T, Browne, C, Dejana, E and Koopman, P (2009) Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice. DEVELOPMENT, 136 14: 2385-2391. doi:10.1242/dev.034827

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Author Hosking, B
Francois, M
Wilhelm, D
Orsenigo, F
Caprini, A
Svingen, T
Tutt, D
Davidson, T
Browne, C
Dejana, E
Koopman, P
Title Sox7 and Sox17 are strain-specific modifiers of the lymphangiogenic defects caused by Sox18 dysfunction in mice
Journal name DEVELOPMENT   Check publisher's open access policy
ISSN 0950-1991
Publication date 2009-07-01
Year available 2009
Sub-type Article (original research)
DOI 10.1242/dev.034827
Open Access Status File (Publisher version)
Volume 136
Issue 14
Start page 2385
End page 2391
Total pages 7
Editor Iva Greenwald
Place of publication The Company of Biologists
Publisher Cambridge, England, U.K.
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
060403 Developmental Genetics (incl. Sex Determination)
Abstract Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics.
Keyword Genetic modifier
Sox genes
Prox1
Lymphangiogenesis
HLT syndrome
Mouse
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID P01 HL089707
PG/10/83/28610
R01 GM103544
R01 HL064658
MR/J007765/1
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: 2010 Higher Education Research Data Collection
Institute for Molecular Bioscience - Publications
 
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Created: Mon, 01 Mar 2010, 20:53:09 EST by Susan Allen on behalf of Institute for Molecular Bioscience