Mammalian target of rapamycin (mTOR) is aberrantly activated in many cancer types, and two rapamycin derivatives are currently approved by the Food and Drug Administration (FDA) of the United States for treating renal...Mammalian target of rapamycin (mTOR) is aberrantly activated in many cancer types, and two rapamycin derivatives are currently approved by the Food and Drug Administration (FDA) of the United States for treating renal cell carcinoma. Mechanistically, mTOR is hyperactivated in human cancers either due to the genetic activation of its upstream activating signaling pathways or the genetic inactivation of its negative regulators. The tumor suppressor liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), is involved in cell polarity, cell detachment and adhesion, tumor metastasis, and energetic stress response. A key role of LKB1 is to negatively regulate the activity of mTOR complex 1 (mTORC1). This review summarizes the molecular basis of this negative interaction and recent research progress in this area.展开更多
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 a...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 BcI-XL. Importantly, ectopic expression of either BcI-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 BcI-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.展开更多
基金supported by NIH Grant R01-CA140571 (to W.Z.)P01-CA116676 (to W.Z. and P.V.). W.Z. is an Anise McDaniel BrockScholar, Georgia Cancer Coalition Scholar, and American Cancer Research Scholar
文摘Mammalian target of rapamycin (mTOR) is aberrantly activated in many cancer types, and two rapamycin derivatives are currently approved by the Food and Drug Administration (FDA) of the United States for treating renal cell carcinoma. Mechanistically, mTOR is hyperactivated in human cancers either due to the genetic activation of its upstream activating signaling pathways or the genetic inactivation of its negative regulators. The tumor suppressor liver kinase B1 (LKB1), also known as serine/threonine kinase 11 (STK11), is involved in cell polarity, cell detachment and adhesion, tumor metastasis, and energetic stress response. A key role of LKB1 is to negatively regulate the activity of mTOR complex 1 (mTORC1). This review summarizes the molecular basis of this negative interaction and recent research progress in this area.
基金Acknowledgments We thank X Wu （Fudan University） for LckCre mouse and K Wong （Dana-Farber Cancer Institute） for LKB1 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, 2009ZX 10004-105）, the Hi-Tech Research and Development Program of China （2007AA02Z167）, the National Basic Research Program of China （2007CB914504） and the Chinese Academy of Sciences （KSCX 1-YW-R-43, KSCX2-YW-R-10）.
文摘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 BcI-XL. Importantly, ectopic expression of either BcI-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 BcI-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.
