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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Tumor suppressor p53 cooperates with SIRT6 to regulate gluconeogenesis by promoting FoxO1 nuclear exclusion
Ping Zhang1, Bo Tu1, Hua Wang2
1Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Biochemistry and Molecular Biology, Peking University Health Science Center, Beijing 100191, China;
Abstract:
In mammalian cells, tumor suppressor p53 plays critical roles in the regulation of glucose metabolism, including glycolysis and oxidative phosphorylation, but whether and how p53 also regulates gluconeogenesis is less clear. Here, we report that p53 efficiently down-regulates the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), which encode rate-limiting enzymes in gluconeogenesis. Cell-based assays demonstrate the p53-dependent nuclear exclusion of forkhead box protein O1 (FoxO1), a key transcription factor that mediates activation of PCK1 and G6PC, with consequent alleviation of FoxO1-dependent gluconeogenesis. Further mechanistic studies show that p53 directly activates expression of the NAD(+)-dependent histone deacetylase sirtuin 6 (SIRT6), whose interaction with FoxO1 leads to FoxO1 deacetylation and export to the cytoplasm. In support of these observations, p53-mediated FoxO1 nuclear exclusion, down-regulation of PCK1 and G6PC expression, and regulation of glucose levels were confirmed in C57BL/J6 mice and in liver-specific Sirt6 conditional knockout mice. Our results provide insights into mechanisms of metabolism-related p53 functions that may be relevant to tumor suppression.
Insights
The tumor suppressor p53 regulates glucose production by inhibiting key enzymes. This involves p53 activating SIRT6, which then causes the nuclear exclusion of FoxO1, a transcription factor.
Area of Science:
- Cell Biology
- Metabolic Regulation
- Molecular Oncology
Background:
- The tumor suppressor p53 is known to regulate glycolysis and oxidative phosphorylation.
- Its role in regulating gluconeogenesis, the production of glucose, is less understood.
Purpose of the Study:
- To investigate the role of p53 in regulating gluconeogenesis.
- To elucidate the molecular mechanisms by which p53 controls glucose metabolism.
Main Methods:
- Cell-based assays were used to examine the effects of p53 on gluconeogenic enzyme expression.
- Mechanistic studies involved assessing protein-protein interactions and post-translational modifications.
- In vivo studies utilized mouse models, including liver-specific knockout mice.
Main Results:
- p53 was found to down-regulate the expression of phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), key enzymes in gluconeogenesis.
- p53 induced the nuclear exclusion of the transcription factor forkhead box protein O1 (FoxO1), thereby inhibiting gluconeogenesis.
- p53 activates sirtuin 6 (SIRT6), which deacetylates and promotes the cytoplasmic export of FoxO1.
- These findings were validated in mouse models, showing p53's role in regulating glucose levels.
Conclusions:
- p53 directly inhibits gluconeogenesis through the SIRT6-FoxO1 pathway.
- This mechanism highlights a novel aspect of p53's metabolic regulation relevant to tumor suppression.
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