Abstract
LKB1 is a serine/threonine kinase that directly activates the energy sensor AMP-activated protein kinase (AMPK) in response to bioenergetic stress, and mainly acts as a tumor suppressor that controls cell polarity and proliferation. Although LKB1 is expressed in multiple tissues including the thymus and the spleen, its roles in T-cell development and function remain unknown. Here, we show that T-cell-specific deletion of LKB1 resulted in reduced survival of double-positive (DP) thymocytes and impaired generation of both CD4 and CD8 single-positive thymocytes. Disruption of LKB1 not only prevented the activation of AMPK but also impaired the expression of anti-apoptotic protein Bcl-XL. Importantly, ectopic expression of either Bcl-XL or the constitutively active AMPK mutant significantly rescued DP thymocytes from LKB1 deficiency-induced cell death. Moreover, ectopic expression of the constitutively active AMPK mutant was found to restore the expression of Bcl-XL in LKB1-deficient DP thymocytes. These findings identify LKB1 as a critical factor for the survival of DP thymocytes through regulation of AMPK activation and Bcl-XL expression.
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Acknowledgements
We thank X Wu (Fudan University) for LckCre mouse and K Wong (Dana-Farber Cancer Institute) for LKB1fl/fl mouse, R Bosselut (National Institutes of Health) and D Li (Shanghai Institutes for Biological Sciences) for instructive comments on the manuscript; We are grateful to our colleagues F Liu for animal husbandry, W Bian for cell sorting and X Wang for real-time PCR analysis. This research was supported in part by the National Natural Science Foundation of China (30872290, 30925031), the Ministry of Science and Technology (2006CB504303, 2007CB815802, 2009ZX10004-105), the Hi-Tech Research and Development Program of China (2007AA02Z167), the National Basic Research Program of China (2007CB914504) and the Chinese Academy of Sciences (KSCX1-YW-R-43, KSCX2-YW-R-10).
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GFP has no effect on thymocyte survival (PDF 67 kb)
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List of primers used for PCR analysis. (PDF 37 kb)
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Cao, Y., Li, H., Liu, H. et al. The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression. Cell Res 20, 99–108 (2010). https://doi.org/10.1038/cr.2009.141
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DOI: https://doi.org/10.1038/cr.2009.141
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