Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Mattias Kalén, Elisabet Wallgard, Noomi Asker, Aidas Nasevicius, Elisabet Athley, Erik Billgren, Jon D. Larson, Shannon A. Wadman, Elizabeth Norseng, Karl J. Clark, Liqun He, Linda Karlsson-Lindahl, Ann Katrin Häger, Holger Weber, Hellmut Augustin, Tore Samuelsson, Chelsy K. Kemmet, Carly M. Utesch, Jeffrey J. Essner, Perry B. HackettMats Hellström

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.

Original languageEnglish (US)
Pages (from-to)432-441
Number of pages10
JournalChemistry and Biology
Volume16
Issue number4
DOIs
StatePublished - Apr 24 2009

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Reverse Genetics
Angiogenesis Inhibitors
Genes
Phosphoprotein Phosphatases
Blood vessels
Biological systems
Assays
Cells
Zebrafish
Microvessels
Pharmaceutical Preparations
Blood Vessels
Vertebrates
Genetics
endothall

Keywords

  • CELLBIO
  • CHEMBIO
  • SIGNALING

Cite this

Kalén, M., Wallgard, E., Asker, N., Nasevicius, A., Athley, E., Billgren, E., ... Hellström, M. (2009). Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets. Chemistry and Biology, 16(4), 432-441. https://doi.org/10.1016/j.chembiol.2009.02.010

Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets. / Kalén, Mattias; Wallgard, Elisabet; Asker, Noomi; Nasevicius, Aidas; Athley, Elisabet; Billgren, Erik; Larson, Jon D.; Wadman, Shannon A.; Norseng, Elizabeth; Clark, Karl J.; He, Liqun; Karlsson-Lindahl, Linda; Häger, Ann Katrin; Weber, Holger; Augustin, Hellmut; Samuelsson, Tore; Kemmet, Chelsy K.; Utesch, Carly M.; Essner, Jeffrey J.; Hackett, Perry B.; Hellström, Mats.

In: Chemistry and Biology, Vol. 16, No. 4, 24.04.2009, p. 432-441.

Research output: Contribution to journalArticle

Kalén, M, Wallgard, E, Asker, N, Nasevicius, A, Athley, E, Billgren, E, Larson, JD, Wadman, SA, Norseng, E, Clark, KJ, He, L, Karlsson-Lindahl, L, Häger, AK, Weber, H, Augustin, H, Samuelsson, T, Kemmet, CK, Utesch, CM, Essner, JJ, Hackett, PB & Hellström, M 2009, 'Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets', Chemistry and Biology, vol. 16, no. 4, pp. 432-441. https://doi.org/10.1016/j.chembiol.2009.02.010
Kalén, Mattias ; Wallgard, Elisabet ; Asker, Noomi ; Nasevicius, Aidas ; Athley, Elisabet ; Billgren, Erik ; Larson, Jon D. ; Wadman, Shannon A. ; Norseng, Elizabeth ; Clark, Karl J. ; He, Liqun ; Karlsson-Lindahl, Linda ; Häger, Ann Katrin ; Weber, Holger ; Augustin, Hellmut ; Samuelsson, Tore ; Kemmet, Chelsy K. ; Utesch, Carly M. ; Essner, Jeffrey J. ; Hackett, Perry B. ; Hellström, Mats. / Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets. In: Chemistry and Biology. 2009 ; Vol. 16, No. 4. pp. 432-441.
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