Endostatin's antiangiogenic signaling network.
It is here demonstrated that the set of gene expressions underlying the angiogenic balance in tissues can be molecularly reset en masse by a single protein. Using genome-wide expression profiling, coupled with RT-PCR and phosphorylation analysis, we show that the endogenous angiogenesis inhibitor endostatin downregulates many signaling pathways in human microvascular endothelium associated with proangiogenic activity. Simultaneously, endostatin is found to upregulate many antiangiogenic genes. The result is a unique alignment between the direction of gene regulation and angiogenic status. Profiling further reveals the regulation of genes not heretofore associated with angiogenesis. Our analysis of coregulated genes shows complex interpathway communications in an intricate signaling network that both recapitulates and extends on current understanding of the angiogenic process. More generally, insights into the nature of genetic networking from the cell biologic and therapeutic perspectives are revealed.
Abdollahi
Amir
A
Department of Radiation Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Hahnfeldt
Philip
P
Maercker
Christian
C
Gröne
Hermann-Josef
HJ
Debus
Juergen
J
Ansorge
Wilhelm
W
Folkman
Judah
J
Hlatky
Lynn
L
Huber
Peter E
PE
D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D043169:Endostatins / Q000235:genetics / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D036342:Ephrins / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051798:Inhibitor of Differentiation Protein 1; D016328:NF-kappa B / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics*; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
D004268:DNA-Binding Proteins; D043169:Endostatins; D036342:Ephrins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha