Identification of proangiogenic genes and pathways by high-throughput functional genomics: TBK1 and the IRF3 pathway.
A genome-wide phenotype screen was used to identify factors and pathways that induce proliferation of human umbilical vein endothelial cells (HUVEC). HUVEC proliferation is a recognized marker for factors that modulate vascularization. Screening "hits" included known proangiogenic factors, such as VEGF, FGF1, and FGF2 and additional factors for which a direct association with angiogenesis was not previously described. These include the kinase TBK1 as well as Toll-like receptor adaptor molecule and IFN regulatory factor 3. All three proteins belong to one signaling pathway that mediates induction of gene expression, including a mixture of secreted factors, which, in concert, mediate proliferative activity toward endothelial cells. TBK1 as the "trigger" of this pathway is induced under hypoxic conditions and expressed at significant levels in many solid tumors. This pattern of expression and the decreased expression of angiogenic factors in cultured cells upon RNA-interference-mediated ablation suggests that TBK1 is important for vascularization and subsequent tumor growth and a target for cancer therapy.
Korherr
Christian
C
Xantos Biomedicine AG, Max-Lebsche-Platz 31, D-81377 München, Germany. c.korherr@xantos.de
Gille
Hendrik
H
Schäfer
Rolf
R
Koenig-Hoffmann
Kerstin
K
Dixelius
Johan
J
Egland
Kristi A
KA
Pastan
Ira
I
Brinkmann
Ulrich
U
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000502:physiology; D001483:Base Sequence; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D018076:DNA, Complementary / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D015870:Gene Expression; D023281:Genomics; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics* / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction; D014162:Transfection
D033942:Adaptor Proteins, Vesicular Transport; D018076:DNA, Complementary; C494232:IRF3 protein, human; D050838:Interferon Regulatory Factor-3; D016328:NF-kappa B; C470409:TICAM1 protein, human; D017346:Protein Serine-Threonine Kinases; C403191:TBK1 protein, human