TP53 Regulates Metabolic Genes (Homo sapiens)

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4, 16, 19, 28, 29, 32...5, 7, 18, 36, 58...84, 9140, 47, 7023, 41, 8029, 65, 89, 9068, 786, 52, 62, 739, 22, 25, 42, 62...3, 35, 4617, 746713, 38, 5415, 29, 65, 90558114, 982, 241, 39, 59, 82, 9419, 5410, 31, 632, 718, 34, 827327, 934, 96, 9784, 9128, 72, 958695559812, 924, 8347, 51lysosomal lumenmitochondrial intermembrane spacecytosolmitochondrial matrixnucleoplasmPRKAG1 Detoxification ofReactive OxygenSpeciesGDP GLS2 dimermiR-26A2 PIP3 activates AKTsignalingCOX7B Metabolism of aminoacids andderivativesTP63/T53:DDIT4 GeneYWHAE H2O2RRAGA COX6A1 EIF2C2 PTEN gene COX4I1 p-T174-PRKAA1 p-T172-PRKAA2 ferriheme TP53Tetramer:SESN1,2,3GenesPiCOX6C(3-75) LRPPRC TNXRD1:FAD dimermiR-26A1 SESN1 Gene MTOR COX5A miR-26A2 p-S939,T1462-TSC2TSC1 GSSGTP63 YWHAQ LAMTOR3 CuA Metabolism ofcarbohydratesPRKAB2 Active AKTDDIT4 Gene PRKAG3 SESN3 H2O2xHC-TXNFru(6)PHOOS-C52-PRDX1 DDIT4YWHAB SFN MT-CO3 GPI dimerYWHAG SLC38A9 EIF2C3 PRKAB1 Cytochrome c(oxidised)TP53 Tetramer:PTENGeneMOV10 COX8A GSR-2 YWHAG SESN1,2,3:HOOS-C52-PRDX1 dimerCytochrome c oxidaseTSC2TNRC6C HOOS-C52-PRDX1 Active mTORC1complexSESN1-1,SESN1-3 TIGAR GeneCOX20 NADPHCOX18 SESN2 Gene TP53 PRDX1 dimerSCO2 COX6B1 SCO2 Gene PRDX1 ATPmiR-26A1 MLST8 SESN3 Gene RRM2BSFN PTEN mRNA:miR-26ARISCNADPHLAMTOR1 NADP+ G6PD dimer andtetramerFAD p-T172-PRKAA2 TP53 Tetramer:SCO2GeneL-GlnYWHAZ TP53 DDIT4 p-S1387-TSC2 TSC1 GPX2 tetramerTXNCOX19PRDX5 p-AMPKheterotrimer:AMPRespiratory electrontransport, ATPsynthesis bychemiosmoticcoupling, and heatproduction byuncouplingproteins.TP53 TetramerH+SURF1 EIF2C1 Cytochrome c(reduced)MT-CO1 RRAGA YWHAQ RRAGB TP53 SESN2 SESN1,2,3:p-AMPKheterotrimer:AMPTP53 PRDX1 SESN1-1,SESN1-3 YWHAQ Metabolism ofnucleotidesRRAGC SESN1-1,SESN1-3 AMP COX7A2L RPTOR H2OTP53 GSR-2:FAD dimerD-Fructose2,6-bisphosphateTNRC6A TP53 GLS2 RHEB TP53 Tetramer:TIGARGenePRDX2 GPX2 YWHAZ PRKAG2 SESN3 NADP+miR-26A RISCMLST8 MT-CO2 NDUFA4 TP53 TNRC6C MOV10 TXNRD1 GLS dimersPiTP63 SCO2RPTOR LAMTOR5 YWHAH H+EIF2C3 TACO1 LAMTOR3 Energy dependentregulation of mTORby LKB1-AMPKGPI SESN3 G6PD PRDX1,2,5RRAGD GluYWHAE SCO2 Genep-T308,S473-AKT1 YWHAE H2OSESN2 Gene GTP H2OSESN2 RRM2B GeneCOX14 LAMTOR4 PRKAG2 COX11 SESN1,2,3FAD PTEN mRNA O2COX5B H+YWHAG TP63 Tetramer/ TP53TetramerGLS2 Gene PRDX1 YWHAZ PRKAB1 14-3-3 dimerSESN3 Gene GLS2 GeneNH4+GLS EIF2C2 TP53 Tetramer:GLS2GeneDDIT4:14-3-3 dimerPTEN geneTNRC6B p-S939,T1462-TSC2 SCO1 AMP ferroheme GSHCOX11,14,16,18,20TIGAR Gene p-S939,T1462-TSC2:14-3-3 dimerADPLAMTOR4 GLS2 RRM2B Gene DDIT4 GeneTSC1:p-S1387-TSC2PRKAG3 MTOR LAMTOR5 EIF2C4 TIGARPTENp-T309,S474-AKT2 PTEN mRNACYCS SESN1 Gene CYCS RRAGD ATPYWHAB SESN1,2,3 Genesp-T174-PRKAA1 TSC2 YWHAB NADP+HOOS-C52-PRDX1 dimerLAMTOR2 TSC1COX16 EIF2C1 PRKAB2 SFN GDP EIF2C4 YWHAH RHEB D-Glucono-1,5-lactone 6-phosphateTSC1:TSC2H2OPRDX1 SLC38A9 COX7C COX ancilliaryproteinsGTP RRAGB TNRC6A YWHAH ADPLAMTOR2 mTORC1:Ragulator:Rag:GNP:RHEB:GDPPRKAG1 G6PSESN2 TP53 H2OTP53 Tetramer:RRM2BGeneTNRC6B H+RRAGC TP53 LAMTOR1 p-T305,S472-AKT3 47, 51707773955449147, 558220, 21, 26, 37, 44...2, 2430, 50, 6929, 65, 9011, 45, 57


While the p53 tumor suppressor protein (TP53) is known to inhibit cell growth by inducing apoptosis, senescence and cell cycle arrest, recent studies have found that p53 is also able to influence cell metabolism to prevent tumor development. TP53 regulates transcription of many genes involved in the metabolism of carbohydrates, nucleotides and amino acids, protein synthesis and aerobic respiration.

TP53 stimulates transcription of TIGAR, a D-fructose 2,6-bisphosphatase. TIGAR activity decreases glycolytic rate and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006). TP53 may also negatively regulate the rate of glycolysis by inhibiting the expression of glucose transporters GLUT1, GLUT3 and GLUT4 (Kondoh et al. 2005, Schwartzenberg-Bar-Yoseph et al. 2004, Kawauchi et al. 2008).<p>TP53 negatively regulates several key points in PI3K/AKT signaling and downstream mTOR signaling, decreasing the rate of protein synthesis and, hence, cellular growth. TP53 directly stimulates transcription of the tumor suppressor PTEN, which acts to inhibit PI3K-mediated activation of AKT (Stambolic et al. 2001). TP53 stimulates transcription of sestrin genes, SESN1, SESN2, and SESN3 (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007). One of sestrin functions may be to reduce and reactivate overoxidized peroxiredoxin PRDX1, thereby reducing ROS levels (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009). Another function of sestrins is to bind the activated AMPK complex and protect it from AKT-mediated inactivation. By enhancing AMPK activity, sestrins negatively regulate mTOR signaling (Budanov and Karin 2008, Cam et al. 2014). The expression of DDIT4 (REDD1), another negative regulator of mTOR signaling, is directly stimulated by TP63 and TP53. DDIT4 prevents AKT-mediated inactivation of TSC1:TSC2 complex, thus inhibiting mTOR cascade (Cam et al. 2014, Ellisen et al. 2002, DeYoung et al. 2008). TP53 may also be involved, directly or indirectly, in regulation of expression of other participants of PI3K/AKT/mTOR signaling, such as PIK3CA (Singh et al. 2002), TSC2 and AMPKB (Feng et al. 2007). <p>TP53 regulates mitochondrial metabolism through several routes. TP53 stimulates transcription of SCO2 gene, which encodes a mitochondrial cytochrome c oxidase assembly protein (Matoba et al. 2006). TP53 stimulates transcription of RRM2B gene, which encodes a subunit of the ribonucleotide reductase complex, responsible for the conversion of ribonucleotides to deoxyribonucleotides and essential for the maintenance of mitochondrial DNA content in the cell (Tanaka et al. 2000, Bourdon et al. 2007, Kulawiec et al. 2009). TP53 also transactivates mitochondrial transcription factor A (TFAM), a nuclear-encoded gene important for mitochondrial DNA (mtDNA) transcription and maintenance (Park et al. 2009). Finally, TP53 stimulates transcription of the mitochondrial glutaminase GLS2, leading to increased mitochondrial respiration rate and reduced ROS levels (Hu et al. 2010). <p>The great majority of tumor cells generate energy through aerobic glycolysis, rather than the much more efficient aerobic mitochondrial respiration, and this metabolic change is known as the Warburg effect (Warburg 1956). Since the majority of tumor cells have impaired TP53 function, and TP53 regulates a number of genes involved in glycolysis and mitochondrial respiration, it is likely that TP53 inactivation plays an important role in the metabolic derangement of cancer cells such as the Warburg effect and the concomitant increased tumorigenicity (reviewed by Feng and Levine 2010). On the other hand, some mutations of TP53 in Li-Fraumeni syndrome may result in the retention of its wild-type metabolic activities while losing cell cycle and apoptosis functions (Wang et al. 2013). Consistent with such human data, some mutations of p53, unlike p53 null state, retain the ability to regulate energy metabolism while being inactive in regulating its classic gene targets involved in cell cycle, apoptosis and senescence. Retention of metabolic and antioxidant functions of p53 protects p53 mutant mice from early onset tumorigenesis (Li et al. 2012). View original pathway at:Reactome.</div>


Pathway is converted from Reactome ID: 5628897
Reactome version: 61
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Reactome Author: Orlic-Milacic, Marija

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