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The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish

Velden, Y.U. and Wang, L. and Zevenhoven, J. and Rooijen van, E. and Lohuizen van, M. and Giles, R.H. and Clevers, H. and Haramis, A.P. (2011) The serine-threonine kinase LKB1 is essential for survival under energetic stress in zebrafish. Proceedings of the National Academy of Sciences of the United States of America, 108, 4358-63. ISSN 0027-8424.

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Official URL: http://dx.doi.org/10.1073/pnas.1010210108

Abstract

Mutations in the serine-threonine kinase (LKB1) lead to a gastrointestinal hamartomatous polyposis disorder with increased predisposition to cancer (Peutz-Jeghers syndrome). LKB1 has many targets, including the AMP-activated protein kinase (AMPK) that is phosphorylated under low-energy conditions. AMPK phosphorylation in turn, affects several processes, including inhibition of the target of rapamycin (TOR) pathway, and leads to proliferation inhibition. To gain insight into how LKB1 mediates its effects during development, we generated zebrafish mutants in the single LKB1 ortholog. We show that in zebrafish lkb1 is dispensable for embryonic survival but becomes essential under conditions of energetic stress. After yolk absorption, lkb1 mutants rapidly exhaust their energy resources and die prematurely from starvation. Notably, intestinal epithelial cells were polarized properly in the lkb1 mutants. We show that attenuation of metabolic rate in lkb1 mutants, either by application of the TOR inhibitor rapamycin or by crossing with von Hippel-Lindau (vhl) mutant fish (in which constitutive hypoxia signaling results in reduced metabolic rate), suppresses key aspects of the lkb1 phenotype. Thus, we demonstrate a critical role for LKB1 in regulating energy homeostasis at the whole-organism level in a vertebrate. Zebrafish models of Lkb1 inactivation could provide a platform for chemical genetic screens to identify compounds that target accelerated metabolism, a key feature of tumor cells.

Item Type:Article
Institutes:Hubrecht Instituut
ID Code:12617
Deposited On:07 Sep 2012 14:19
Last Modified:19 Sep 2012 16:37

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