p53-Dependent regulation of metabolic function through transcriptional activation of pantothenate kinase-1 gene.
It is well established that the p53 tumor suppressor plays a crucial role in controlling cell proliferation and apoptosis upon various types of stress. There is increasing evidence showing that p53 is also critically involved in various metabolic pathways, both in tumor and normal cells. Here, we have identified a novel p53 metabolic target pantothenate kinase-1 (PANK1) via ChIP-on-chip. PanK1 catalyzes the rate-limiting step for CoA synthesis and, therefore, controls intracellular CoA content; Pank1-knockout mice exhibit defect in β-oxidation and gluconeogenesis in the liver after starvation due to insufficient CoA levels. We demonstrated that PANK1 gene is a direct transcriptional target of p53. Although DNA damage-induced p53 upregulates PanK1 expression, depletion of PanK1 expression does not affect p53-dependent growth arrest or apoptosis. Interestingly, upon glucose starvation, PanK1 expression is significantly reduced in HCT116 p53 (-/-) but not in HCT116 p53 (+/+) cells, suggesting that p53 is required to maintain PanK1 expression under metabolic stress conditions. Moreover, by using p53-mutant mice, we observed that, similar to the case in Pank1-knockout mice, gluconeogenesis is partially impaired in p53-null mice. Together, our findings show that p53 plays an important role in regulating energy homeostasis through transcriptional control of PANK1, independent of its canonical functions in apoptosis and cell cycle arrest.
Institute for Cancer Genetics and Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Shang-Jui
SJ
Wang
Guowu
G
Yu
Le
L
Jiang
Tongyuan
T
Li
Qing
Q
Lin
Yi
Y
Tang
Wei
W
Gu
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D004249:DNA Damage / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D005943:Gluconeogenesis / Q000235:genetics; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
D016159:Tumor Suppressor Protein p53; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase
PanK1; apoptosis and gluconeogenesis; cell cycle arrest; metabolism; p53