Ribosomal protein–Mdm2–p53 pathway coordinates nutrient stress with lipid metabolism by regulating MCD and promoting fatty acid oxidation

Abstract

The tumor suppressor p53 has recently been shown to regulate energy metabolism through multiple mechanisms. However, the in vivo signaling pathways related to p53-mediated metabolic regulation remain largely uncharacterized. By using mice bearing a single amino acid substitution at cysteine residue 305 of mouse double minute 2 (Mdm2 C305F ), which renders Mdm2 deficient in binding ribosomal proteins (RPs) RPL11 and RPL5, we show that the RP-Mdm2-p53 signaling pathway is critical for sensing nutrient deprivation and maintaining liver lipid homeostasis. Although the Mdm2 C305F mutation does not significantly affect growth and development in mice, this mutation promotes fat accumulation under normal feeding conditions and hepatosteatosis under acute fasting conditions. We show that nutrient deprivation inhibits rRNA biosynthesis, increases RP-Mdm2 interaction, and induces p53-mediated transactivation of malonyl-CoA decarboxylase (MCD), which catalyzes the degradation of malonyl-CoA to acetyl-CoA, thus modulating lipid partitioning. Fasted Mdm2 C305F mice demonstrate attenuated MCD induction and enhanced malonylCoA accumulation in addition to decreased oxidative respiration and increased fatty acid accumulation in the liver. Thus, the RPMdm2-p53 pathway appears to function as an endogenous sensor responsible for stimulating fatty acid oxidation in response to nutrient depletion.T he dynamic process of cell growth and division is under constant surveillance. As one of the primary "gatekeepers" of the cell, p53 plays a major role in sensing and responding to a variety of internal and external stressors to maintain cellular homeostasis. In addition to its conventional roles in promoting cell cycle arrest, senescence, and apoptosis, p53 has recently been shown to regulate metabolism through the transcriptional activation of genes involved in glucose transport, glycolysis, oxidative phosphorylation (OXPHOS), and glutamine hydrolysis as well as in the activation of genes upstream of the mammalian target of rapamycin and autophagic pathways (reviewed in ref.1). Virtually all cancers show metabolic changes that result in enhanced glucose consumption and elevated glycolytic activity known as the Warburg effect (2). Because cells continuously undergo metabolic perturbations as a result of constantly changing physiological and environmental cues such as daily feeding/fasting cycles, p53 may act in this context as a metabolic stress regulator altering cellular metabolic programs under nonlethal or "low-stress" conditions. Recent studies have shown that inhibition of ribosomal biogenesis can activate p53 through the ribosomal protein (RP)-mediated suppression of mouse double minute 2 (Mdm2) in the RP-Mdm2-p53 stress response pathway (3). Detailed analysis revealed that several RPs require the Mdm2 central zinc finger motif for efficient Mdm2 binding. Interestingly, cancer-associated MDM2 mutations have been reported to affect the central zinc finger motif (4, 5) and can specifically disrupt RP binding (6). To study the physiolog...

p53: Protection against Tumor Growth beyond Effects on Cell Cycle and Apoptosis

“…Lipin1 is a recently identified p53 target gene that regulates the expression of genes involved in fatty acid oxidation through PPARa (14). Under nutrient/glucose deprivation conditions, p53 is upregulated by AMPK and stimulates Lipin1 and malonyl-CoA decarboxylase expression, leading to an increase in fatty acid oxidation (14,15). This allows cells to use fatty acids as an alternative energy source.…”

Degrons in cancer

“…This pathway enables the appropriate response to a range of stress factors, especially those that cause DNA damage, such as ionizing and ultraviolet (UV) radiation and genotoxic agents. Furthermore, the p53 pathway is also involved in the cell's reaction to nutrient deprivation (129,130), hypoxia (129), and thermal shock (131,132). The outcome from the activation of the p53 pathway can be either cell cycle arrest, which provides the necessary time frame Positional density of degrons in protein sequences Fig.…”

Chaperoning 5S RNA assembly

“…The 5S RNP binds to and inhibits MDM2, resulting in the stabilization and activation of p53. This pathway regulates energy metabolism, senses nucleolar stress such as impairment of ribosome biogenesis, and is an essential control for oncogene overexpression (Donati et al 2013;Sloan et al 2013;Liu et al 2014). The regulation of the 5S RNP/p53 pathway plays a major role in ribosomopathies, such as Diamond Blackfan anemia, 5q syndrome, and Treacher Collins syndrome, which are believed to be caused by the misregulation of p53.…”