Glucose Starvation Induces Apoptosis of TSC-/- cells in a p53-dependentGlucose Starvation Induces Apoptosis of TSC-/- cells in a p53-dependentManner.

MTOR;Apoptosis;P53;Rapamycin;Biological Chemistry

Lee, Chung-HanWang, Cun-Yu ;

University of Michigan

关键词: MTOR;    Apoptosis;    P53;    Rapamycin;    Biological Chemistry;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/62191/chunghl_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Tuberous Sclerosis Complex (TSC) is associated with uncontrolled mTOR activation and hamartoma formation.We show that glucose starvation induces apoptosis in TSC cells in a p53-dependent manner.In normal cells, energy starvation induces AMPK-dependent phosphorylation and stabilization of p53.However, the elevation of p53 is limited by AMPK-dependent inhibition of mTOR, which regulates p53 translation.The limited accumulation of p53 protects the cells from stress conditions.In contrast, TSC cells, which are defective in energy starvation-induced mTOR inhibition, show dramatic accumulation of p53, which is due to AMPK-dependent stabilization and continued translation of p53 by active mTOR.Consequently, the high levels of p53 accumulation induce apoptosis.Our data establish the functions of TSC1/2 and p53 in cellular energy response, and provide a possible explanation for the benign nature of hamartoma in TSC.TSC tumors are not only benign but also highly apoptotic.When mTOR is constitutively active, cells are more sensitive to energy starvation related stresses, which can be induced by both glucose deprivation and hypoxia.However, the mechanism for this phenomenon is not clearly understood.Although mTOR inhibitors are currently being tested for anti-neoplastic therapy, here we explore a context where mTOR inhibition is protective instead of pro-apoptotic in TSC-/- cells.The increased sensitivity to apoptosis may be explained by a mechanistic linkage between the mTOR and p53 pathways.p53 is one of the most highly mutated tumor suppressor genes in human cancers, and this link between the mTOR and p53 pathways suggests that p53 status may be important for sensitivity to mTOR inhibition.