dc.contributor.author
Klaus, Miriam
dc.contributor.author
Prokoph, Nina
dc.contributor.author
Girbig, Mathias
dc.contributor.author
Wang, Xuecong
dc.contributor.author
Huang, Yong-Heng
dc.contributor.author
Srivastava, Yogesh
dc.contributor.author
Hou, Linlin
dc.contributor.author
Narasimhan, Kamesh
dc.contributor.author
Kolatkar, Prasanna R.
dc.contributor.author
Francois, Mathias
dc.contributor.author
Jauch, Ralf
dc.date.accessioned
2018-06-08T02:56:51Z
dc.date.available
2016-07-05T12:29:06.169Z
dc.identifier.uri
https://refubium.fu-berlin.de/handle/fub188/14189
dc.identifier.uri
http://dx.doi.org/10.17169/refubium-18386
dc.description.abstract
The transcription factor (TF) SOX18 drives lymphatic vessel development in
both embryogenesis and tumour-induced neo-lymphangiogenesis. Genetic
disruption of Sox18 in a mouse model protects from tumour metastasis and
established the SOX18 protein as a molecular target. Here, we report the
crystal structure of the SOX18 DNA binding high-mobility group (HMG) box bound
to a DNA element regulating Prox1 transcription. The crystals diffracted to
1.75Å presenting the highest resolution structure of a SOX/DNA complex
presently available revealing water structure, structural adjustments at the
DNA contact interface and non-canonical conformations of the DNA backbone. To
explore alternatives to challenging small molecule approaches for targeting
the DNA-binding activity of SOX18, we designed a set of five decoys based on
modified Prox1-DNA. Four decoys potently inhibited DNA binding of SOX18 in
vitro and did not interact with non-SOX TFs. Serum stability, nuclease
resistance and thermal denaturation assays demonstrated that a decoy
circularized with a hexaethylene glycol linker and terminal phosphorothioate
modifications is most stable. This SOX decoy also interfered with the
expression of a luciferase reporter under control of a SOX18-dependent VCAM1
promoter in COS7 cells. Collectively, we propose SOX decoys as potential
strategy for inhibiting SOX18 activity to disrupt tumour-induced neo-
lymphangiogenesis.
en
dc.rights.uri
http://creativecommons.org/licenses/by-nc/4.0/
dc.subject.ddc
500 Naturwissenschaften und Mathematik::570 Biowissenschaften; Biologie::572 Biochemie
dc.title
Structure and decoy-mediated inhibition of the SOX18/Prox1-DNA interaction
dc.type
Wissenschaftlicher Artikel
dcterms.bibliographicCitation
Nucleic Acids Research. - 44 (2016), 8, S. 3922-3935
dcterms.bibliographicCitation.doi
10.1093/nar/gkw130
dcterms.bibliographicCitation.url
http://nar.oxfordjournals.org/content/44/8/3922
refubium.affiliation
Biologie, Chemie, Pharmazie
de
refubium.mycore.fudocsId
FUDOCS_document_000000024947
refubium.note.author
Der Artikel wurde in einer Open-Access-Zeitschrift publiziert.
refubium.resourceType.isindependentpub
no
refubium.mycore.derivateId
FUDOCS_derivate_000000006723
dcterms.accessRights.openaire
open access