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Science 293 (5533): 1323-1326

Copyright © 2001 by the American Association for the Advancement of Science

Vascular Abnormalities and Deregulation of VEGF in Lkb1-Deficient Mice

Antti Ylikorkala,1* Derrick J. Rossi,1* Nina Korsisaari,1 Keijo Luukko,2 Kari Alitalo,13 Mark Henkemeyer,4 Tomi P. Mäkelä13dagger

The LKB1 tumor suppressor gene, mutated in Peutz-Jeghers syndrome, encodes a serine/threonine kinase of unknown function. Here we show that mice with a targeted disruption of Lkb1 die at midgestation, with the embryos showing neural tube defects, mesenchymal cell death, and vascular abnormalities. Extraembryonic development was also severely affected; the mutant placentas exhibited defective labyrinth layer development and the fetal vessels failed to invade the placenta. These phenotypes were associated with tissue-specific deregulation of vascular endothelial growth factor (VEGF) expression, including a marked increase in the amount of VEGF messenger RNA. Moreover, VEGF production in cultured Lkb1-/- fibroblasts was elevated in both normoxic and hypoxic conditions. These findings place Lkb1 in the VEGF signaling pathway and suggest that the vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.

1 Molecular and Cancer Biology Program, Haartman Institute and Biomedicum Helsinki, Post Office Box 63, University of Helsinki, Helsinki 00014, Finland.
2 Department of Anatomy and Cell Biology, University of Bergen N-5009 Bergen, Norway.
3 Helsinki University Central Hospital Laboratory Diagnostics, Post Office Box 401, Helsinki 00029 HYKS, Finland.
4 Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75235-9133, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: tomi.makela{at}

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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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K.-i. Jishage, J.-i. Nezu, Y. Kawase, T. Iwata, M. Watanabe, A. Miyoshi, A. Ose, K. Habu, T. Kake, N. Kamada, et al. (2002)
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »
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   Abstract »    Full Text »    PDF »

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