TP53 Regulates Metabolic Genes (Homo sapiens)

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2, 6, 13, 16, 17, 22...218, 9825, 37, 43, 9575, 9256, 716157, 161, 9646, 60, 8542, 49, 55, 63, 9158, 66, 67967, 1652245, 47, 69, 7017, 81, 9423, 3644, 8719, 2611, 24, 25, 35, 37...8, 9313, 30, 7112, 47, 69, 7034, 38, 61256423, 57, 884, 10, 14, 21, 31...27, 9248, 65, 849, 42, 9017, 59lysosomal lumencytosolnucleoplasmmitochondrial matrixmitochondrial intermembrane spaceTP63 Tetramer/ TP53TetramerTNXRD1:FAD dimerTP63/T53:DDIT4 GeneSFN TXNGPI LAMTOR1 NADPHmTORC1:Ragulator:Rag:GNP:RHEB:GDPPRDX1,2,5SESN2 Gene COX6A1 GLS dimersYWHAE COX5B TP53Tetramer:SESN1,2,3GenesAGO2 PRDX1 p-T309,S474-AKT2 ferriheme HOOS-C52-PRDX1 dimerRRM2Bp-T174-PRKAA1 TP53 H2OGTP TSC1 RPTOR TP53 p-AMPKheterotrimer:AMPCOX18 miR-26A1 DDIT4 GeneTNRC6B TP53 TP53 TP53 H2OPRKAB1 p-T308,S473-AKT1 FAD AMP NDUFA4 SCO2DDIT4:14-3-3 dimerPRKAB2 H+TP53 COX8A PRKAG2 SESN1-1,SESN1-3 YWHAG TNRC6C PTEN mRNA TACO1 p-S1387-TSC2 14-3-3 dimerTP53 Tetramer:RRM2BGeneTP53 Tetramer:SCO2GeneYWHAH SESN3 Gene SFN RRM2B Gene YWHAH TIGAR GeneCYCS SESN1-1,SESN1-3 EIF2C4 PTEN mRNA:miR-26ARISCMetabolism ofcarbohydratesp-T305,S472-AKT3 Cytochrome c oxidaseH2OH+RRAGA GSR-2 p-S939,T1462-TSC2RRAGD PRKAB1 GPX2 tetramerTSC1 RPTOR GLS2 LAMTOR4 Metabolism of aminoacids andderivativesTSC1MT-CO2 COX14 TP53 SFN YWHAZ H2O2RHEB SESN1-1,SESN1-3 O2SCO2 GenePTENSCO2 Gene TP53 SESN1 Gene ADPD-Fructose2,6-bisphosphateSESN1,2,3 GenesRHEB H2OTNRC6B L-GlnMOV10 HOOS-C52-PRDX1 SESN2 Gene 2xHC-TXNYWHAH p-T,p-S-AKTH2OGLS2 GeneRespiratory electrontransport, ATPsynthesis bychemiosmoticcoupling, and heatproduction byuncouplingproteins.SESN1,2,3TNRC6A GLS2 YWHAB L-Gluferroheme COX ancilliaryproteinsCOX20 miR-26A2 RRAGC EIF2C3 SESN1,2,3:p-AMPKheterotrimer:AMPSURF1 YWHAG RRAGB MOV10 YWHAQ MTOR TP53 Tetramer:GLS2GeneSESN3 TSC2 TP63 NADPHTNRC6C p-S939,T1462-TSC2:14-3-3 dimerNADP+YWHAE DDIT4 GSSGH+TSC1:p-S1387-TSC2CuA miR-26A RISCGSR-2:FAD dimerGLS2 Gene EIF2C1 PRKAG3 YWHAQ LAMTOR3 D-Glucono-1,5-lactone 6-phosphateGDP LAMTOR4 PRDX5 GLS2 dimerYWHAG LRPPRC COX16 PRKAG1 PRDX1 G6PD dimer andtetramerMLST8 PIP3 activates AKTsignalingPRKAG2 COX5A MT-CO3 RRAGB YWHAZ SCO2 CYCS ATPSESN1,2,3:HOOS-C52-PRDX1 dimerCOX7A2L GDP DDIT4GSHPiYWHAQ EIF2C4 SESN3 Gene PTEN mRNARRAGD COX11,14,16,18,20ATPEIF2C1 GLS TP53 Tetramer:TIGARGeneTP53 TetramerSESN3 SLC38A9 NH4+GPI dimerTP53 Tetramer:PTENGeneMLST8 LAMTOR2 COX7C TP53 SESN2 SESN1 Gene LAMTOR5 HOOS-C52-PRDX1 PRKAG1 NADP+ PTEN geneFru(6)PTSC1:TSC2Energy dependentregulation of mTORby LKB1-AMPKCOX4I1 H+COX7B PiPRDX1 dimerYWHAB COX11 LAMTOR3 TIGARPRKAG3 SESN2 YWHAE LAMTOR1 YWHAB LAMTOR2 TIGAR Gene miR-26A1 YWHAZ COX19TXNRD1 GPX2 EIF2C3 TP63 p-T172-PRKAA2 Detoxification ofReactive OxygenSpeciesMetabolism ofnucleotidesActive mTORC1complexCytochrome c(oxidised)COX6C(3-75) H2ODDIT4 Gene MT-CO1 PTEN gene PRDX1 TSC2p-T172-PRKAA2 ADPPRDX1 G6PD MTOR GTP miR-26A2 AGO2 NADP+SCO1 FAD COX6B1 SESN2 PRDX2 PRKAB2 Cytochrome c(reduced)SESN3 G6PSLC38A9 LAMTOR5 RRAGA RRAGC TNRC6A RRM2B Genep-S939,T1462-TSC2 p-T174-PRKAA1 AMP 1347, 69, 706156, 711627, 92532062, 79, 993, 29, 3315, 32, 40, 41, 54...2523422, 7117


Description

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>

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Reactome Author: Orlic-Milacic, Marija

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History

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102617view08:09, 13 January 2019EgonwAssuming CuA is Cu2+
101405view11:29, 1 November 2018ReactomeTeamreactome version 66
100943view21:05, 31 October 2018ReactomeTeamreactome version 65
100480view19:39, 31 October 2018ReactomeTeamreactome version 64
100025view16:22, 31 October 2018ReactomeTeamreactome version 63
99578view14:55, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99200view12:43, 31 October 2018ReactomeTeamreactome version 62
93881view13:42, 16 August 2017ReactomeTeamreactome version 61
93449view11:23, 9 August 2017ReactomeTeamreactome version 61
88395view15:18, 4 August 2016FehrhartOntology Term : 'classic metabolic pathway' added !
88394view15:16, 4 August 2016FehrhartOntology Term : 'regulatory pathway' added !
86541view09:20, 11 July 2016ReactomeTeamreactome version 56
83329view10:48, 18 November 2015ReactomeTeamVersion54
81482view13:01, 21 August 2015ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
14-3-3 dimerComplexR-HSA-1445138 (Reactome)
2xHC-TXNProteinP10599 (Uniprot-TrEMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
AGO2 ProteinQ9UKV8 (Uniprot-TrEMBL)
AMP MetaboliteCHEBI:16027 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
Active mTORC1 complexComplexR-HSA-165678 (Reactome)
COX ancilliary proteinsComplexR-HSA-5566488 (Reactome)
COX11 ProteinQ9Y6N1 (Uniprot-TrEMBL)
COX11,14,16,18,20ComplexR-HSA-5336143 (Reactome)
COX14 ProteinQ96I36 (Uniprot-TrEMBL)
COX16 ProteinQ9P0S2 (Uniprot-TrEMBL)
COX18 ProteinQ8N8Q8 (Uniprot-TrEMBL)
COX19ProteinQ3E731 (Uniprot-TrEMBL)
COX20 ProteinQ5RI15 (Uniprot-TrEMBL)
COX4I1 ProteinP13073 (Uniprot-TrEMBL)
COX5A ProteinP20674 (Uniprot-TrEMBL)
COX5B ProteinP10606 (Uniprot-TrEMBL)
COX6A1 ProteinP12074 (Uniprot-TrEMBL)
COX6B1 ProteinP14854 (Uniprot-TrEMBL)
COX6C(3-75) ProteinP09669 (Uniprot-TrEMBL)
COX7A2L ProteinO14548 (Uniprot-TrEMBL)
COX7B ProteinP24311 (Uniprot-TrEMBL)
COX7C ProteinP15954 (Uniprot-TrEMBL)
COX8A ProteinP10176 (Uniprot-TrEMBL)
CYCS ProteinP99999 (Uniprot-TrEMBL)
CuA MetaboliteCHEBI:29036 (ChEBI)
Cytochrome c (oxidised)ComplexR-HSA-352607 (Reactome)
Cytochrome c (reduced)ComplexR-HSA-352609 (Reactome)
Cytochrome c oxidaseComplexR-HSA-164316 (Reactome)
D-Fructose 2,6-bisphosphateMetaboliteCHEBI:28602 (ChEBI)
D-Glucono-1,5-lactone 6-phosphateMetaboliteCHEBI:16938 (ChEBI)
DDIT4 Gene ProteinENSG00000168209 (Ensembl)
DDIT4 GeneGeneProductENSG00000168209 (Ensembl)
DDIT4 ProteinQ9NX09 (Uniprot-TrEMBL)
DDIT4:14-3-3 dimerComplexR-HSA-5632741 (Reactome)
DDIT4ProteinQ9NX09 (Uniprot-TrEMBL)
Detoxification of

Reactive Oxygen

Species
PathwayR-HSA-3299685 (Reactome) Reactive oxygen species such as superoxide (O2.-), peroxides (ROOR), singlet oxygen, peroxynitrite (ONOO-), and hydroxyl radical (OH.) are generated by cellular processes such as respiration (reviewed in Murphy 2009, Brand 2010) and redox enzymes and are required for signaling yet they are damaging due to their high reactivity (reviewed in Imlay 2008, Buettner 2011, Kavdia 2011, Birben et al. 2012, Ray et al. 2012). Aerobic cells have defenses that detoxify reactive oxygen species by converting them to less reactive products. Superoxide dismutases convert superoxide to hydrogen peroxide and oxygen (reviewed in Fukai and Ushio-Fukai 2011). Catalase and peroxidases then convert hydrogen peroxide to water.
Humans contain 3 superoxide dismutases: SOD1 is located in the cytosol and mitochondrial intermembrane space, SOD2 is located in the mitochondrial matrix, and SOD3 is located in the extracellular region. Superoxide, a negative ion, is unable to easily cross membranes and tends to remain in the compartment where it was produced. Hydrogen peroxide, one of the products of superoxide dismutase, is able to diffuse across membranes and pass through aquaporin channels. In most cells the primary source of hydrogen peroxide is mitochondria and, once in the cytosol, hydrogen peroxide serves as a signaling molecule to regulate redox-sensitive proteins such as transcription factors, kinases, phosphatases, ion channels, and others (reviewed in Veal and Day 2011, Ray et al. 2012). Hydrogen peroxide is decomposed to water by catalase, decomposed to water plus oxidized thioredoxin by peroxiredoxins, and decomposed to water plus oxidized glutathione by glutathione peroxidases (Presnell et al. 2013).
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
Energy dependent

regulation of mTOR

by LKB1-AMPK
PathwayR-HSA-380972 (Reactome) Upon formation of a trimeric LKB1:STRAD:MO25 complex, LKB1 phosphorylates and activates AMPK. This phosphorylation is immediately removed in basal conditions by PP2C, but if the cellular AMP:ATP ratio rises, this activation is maintained, as AMP binding by AMPK inhibits the dephosphorylation. AMPK then activates the TSC complex by phosphorylating TSC2. Active TSC activates the intrinsic GTPase activity of Rheb, resulting in GDP-loaded Rheb and inhibition of mTOR pathway.
FAD MetaboliteCHEBI:16238 (ChEBI)
Fru(6)PMetaboliteCHEBI:15946 (ChEBI)
G6PMetaboliteCHEBI:17665 (ChEBI)
G6PD ProteinP11413 (Uniprot-TrEMBL)
G6PD dimer and tetramerComplexR-HSA-464971 (Reactome)
GDP MetaboliteCHEBI:17552 (ChEBI)
GLS ProteinO94925 (Uniprot-TrEMBL)
GLS dimersComplexR-HSA-507859 (Reactome)
GLS2 Gene ProteinENSG00000135423 (Ensembl)
GLS2 GeneGeneProductENSG00000135423 (Ensembl)
GLS2 ProteinQ9UI32 (Uniprot-TrEMBL)
GLS2 dimerComplexR-HSA-507858 (Reactome)
GPI ProteinP06744 (Uniprot-TrEMBL)
GPI dimerComplexR-HSA-70469 (Reactome)
GPX2 ProteinP18283 (Uniprot-TrEMBL)
GPX2 tetramerComplexR-HSA-2142735 (Reactome)
GSHMetaboliteCHEBI:16856 (ChEBI)
GSR-2 ProteinP00390-2 (Uniprot-TrEMBL)
GSR-2:FAD dimerComplexR-HSA-71680 (Reactome)
GSSGMetaboliteCHEBI:17858 (ChEBI)
GTP MetaboliteCHEBI:15996 (ChEBI)
H+MetaboliteCHEBI:15378 (ChEBI)
H2O2MetaboliteCHEBI:16240 (ChEBI)
H2OMetaboliteCHEBI:15377 (ChEBI)
HOOS-C52-PRDX1 ProteinQ06830 (Uniprot-TrEMBL)
HOOS-C52-PRDX1 dimerComplexR-HSA-5631882 (Reactome)
L-GlnMetaboliteCHEBI:58359 (ChEBI)
L-GluMetaboliteCHEBI:29985 (ChEBI)
LAMTOR1 ProteinQ6IAA8 (Uniprot-TrEMBL)
LAMTOR2 ProteinQ9Y2Q5 (Uniprot-TrEMBL)
LAMTOR3 ProteinQ9UHA4 (Uniprot-TrEMBL)
LAMTOR4 ProteinQ0VGL1 (Uniprot-TrEMBL)
LAMTOR5 ProteinO43504 (Uniprot-TrEMBL)
LRPPRC ProteinP42704 (Uniprot-TrEMBL)
MLST8 ProteinQ9BVC4 (Uniprot-TrEMBL)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
MT-CO1 ProteinP00395 (Uniprot-TrEMBL)
MT-CO2 ProteinP00403 (Uniprot-TrEMBL)
MT-CO3 ProteinP00414 (Uniprot-TrEMBL)
MTOR ProteinP42345 (Uniprot-TrEMBL)
Metabolism of carbohydratesPathwayR-HSA-71387 (Reactome) Starches and sugars are major constituents of the human diet and the catabolism of monosaccharides, notably glucose, derived from them is an essential part of human energy metabolism (Dashty 2013). Glucose can be catabolized to pyruvate (glycolysis) and pyruvate synthesized from diverse sources can be metabolized to form glucose (gluconeogenesis). Glucose can be polymerized to form glycogen under conditions of glucose excess (glycogen synthesis), and glycogen can be broken down to glucose in response to stress or starvation (glycogenolysis). Other monosaccharides prominent in the diet, fructose and galactose, can be converted to glucose. The disaccharide lactose, the major carbohydrate in breast milk, is synthesized in the lactating mammary gland. The pentose phosphate pathway allows the synthesis of diverse monosaccharides from glucose including the pentose ribose-5-phosphate and the regulatory molecule xylulose-5-phosphate, as well as the generation of reducing equivalents for biosynthetic processes. Glycosaminoglycan metabolism and xylulose-5-phosphate synthesis from glucuronate are also annotated as parts of carbohydrate metabolism.

The digestion of dietary starch and sugars and the uptake of the resulting monosaccharides into the circulation from the small intestine are annotated as parts of the “Digestion and absorption� pathway.

Metabolism of nucleotidesPathwayR-HSA-15869 (Reactome) Nucleotides and their derivatives are used for short-term energy storage (ATP, GTP), for intra- and extra-cellular signaling (cAMP; adenosine), as enzyme cofactors (NAD, FAD), and for the synthesis of DNA and RNA. Most dietary nucleotides are consumed by gut flora; the human body's own supply of these molecules is synthesized de novo. Additional metabolic pathways allow the interconversion of nucleotides, the salvage and reutilization of nucleotides released by degradation of DNA and RNA, the catabolism of excess nucleotides, and the transport of these molecules between the cytosol and the nucleus (Rudolph 1994). These pathways are regulated to control the total size of the intracellular nucleotide pool, to balance the relative amounts of individual nucleotides, and to couple the synthesis of deoxyribonucleotides to the onset of DNA replication (S phase of the cell cycle).

These pathways are also of major clinical interest as they are the means by which nucleotide analogues used as anti-viral and anti-tumor drugs are taken up by cells, activated, and catabolized (Weilin and Nordlund 2010). As well, differences in nucleotide metabolic pathways between humans and aplicomplexan parasites like Plasmodium have been exploited to design drugs to attack the latter (Hyde 2007).

The movement of nucleotides and purine and pyrimidine bases across lipid bilayer membranes, mediated by SLC transporters, is annotated as part of the module "transmembrane transport of small molecules".

Metabolism of amino

acids and

derivatives
PathwayR-HSA-71291 (Reactome) This group of reactions is responsible for: 1) the breakdown of amino acids; 2) the synthesis of urea from ammonia and amino groups generated by amino acid breakdown; 3) the synthesis of the ten amino acids that are not essential components of the human diet; and 4) the synthesis of related nitrogen-containing molecules including carnitine and creatine.

Transport of these molecuels across lipid bilayer membranes is annotated separately as part of the module on "transmembrane transport of small molecules".

NADP+ MetaboliteCHEBI:18009 (ChEBI)
NADP+MetaboliteCHEBI:18009 (ChEBI)
NADPHMetaboliteCHEBI:16474 (ChEBI)
NDUFA4 ProteinO00483 (Uniprot-TrEMBL)
NH4+MetaboliteCHEBI:28938 (ChEBI)
O2MetaboliteCHEBI:15379 (ChEBI)
PIP3 activates AKT signalingPathwayR-HSA-1257604 (Reactome) Signaling by AKT is one of the key outcomes of receptor tyrosine kinase (RTK) activation. AKT is activated by the cellular second messenger PIP3, a phospholipid that is generated by PI3K. In ustimulated cells, PI3K class IA enzymes reside in the cytosol as inactive heterodimers composed of p85 regulatory subunit and p110 catalytic subunit. In this complex, p85 stabilizes p110 while inhibiting its catalytic activity. Upon binding of extracellular ligands to RTKs, receptors dimerize and undergo autophosphorylation. The regulatory subunit of PI3K, p85, is recruited to phosphorylated cytosolic RTK domains either directly or indirectly, through adaptor proteins, leading to a conformational change in the PI3K IA heterodimer that relieves inhibition of the p110 catalytic subunit. Activated PI3K IA phosphorylates PIP2, converting it to PIP3; this reaction is negatively regulated by PTEN phosphatase. PIP3 recruits AKT to the plasma membrane, allowing TORC2 to phosphorylate a conserved serine residue of AKT. Phosphorylation of this serine induces a conformation change in AKT, exposing a conserved threonine residue that is then phosphorylated by PDPK1 (PDK1). Phosphorylation of both the threonine and the serine residue is required to fully activate AKT. The active AKT then dissociates from PIP3 and phosphorylates a number of cytosolic and nuclear proteins that play important roles in cell survival and metabolism. For a recent review of AKT signaling, please refer to Manning and Cantley, 2007.
PRDX1 ProteinQ06830 (Uniprot-TrEMBL)
PRDX1 dimerComplexR-HSA-3341319 (Reactome)
PRDX1,2,5ComplexR-HSA-3341359 (Reactome)
PRDX2 ProteinP32119 (Uniprot-TrEMBL)
PRDX5 ProteinP30044-2 (Uniprot-TrEMBL)
PRKAB1 ProteinQ9Y478 (Uniprot-TrEMBL)
PRKAB2 ProteinO43741 (Uniprot-TrEMBL)
PRKAG1 ProteinP54619 (Uniprot-TrEMBL)
PRKAG2 ProteinQ9UGJ0 (Uniprot-TrEMBL)
PRKAG3 ProteinQ9UGI9 (Uniprot-TrEMBL)
PTEN gene ProteinENSG00000171862 (Ensembl)
PTEN geneGeneProductENSG00000171862 (Ensembl)
PTEN mRNA ProteinENST00000371953 (Ensembl)
PTEN mRNA:miR-26A RISCComplexR-HSA-2318750 (Reactome)
PTEN mRNARnaENST00000371953 (Ensembl)
PTENProteinP60484 (Uniprot-TrEMBL)
PiMetaboliteCHEBI:18367 (ChEBI)
RHEB ProteinQ15382 (Uniprot-TrEMBL)
RPTOR ProteinQ8N122 (Uniprot-TrEMBL)
RRAGA ProteinQ7L523 (Uniprot-TrEMBL)
RRAGB ProteinQ5VZM2 (Uniprot-TrEMBL)
RRAGC ProteinQ9HB90 (Uniprot-TrEMBL)
RRAGD ProteinQ9NQL2 (Uniprot-TrEMBL)
RRM2B Gene ProteinENSG00000048392 (Ensembl)
RRM2B GeneGeneProductENSG00000048392 (Ensembl)
RRM2BProteinQ7LG56 (Uniprot-TrEMBL)
Respiratory electron

transport, ATP synthesis by chemiosmotic coupling, and heat production by uncoupling

proteins.
PathwayR-HSA-163200 (Reactome) Oxidation of fatty acids and pyruvate in the mitochondrial matrix yield large amounts of NADH. The respiratory electron transport chain couples the re-oxidation of this NADH to NAD+ to the export of protons from the mitochonrial matrix, generating a chemiosmotic gradient across the inner mitochondrial membrane. This gradient is used to drive the synthesis of ATP; it can also be bypassed by uncoupling proteins to generate heat, a reaction in brown fat that may be important in regulation of body temperature in newborn children.
SCO1 ProteinO75880 (Uniprot-TrEMBL)
SCO2 Gene ProteinENSG00000130489 (Ensembl)
SCO2 GeneGeneProductENSG00000130489 (Ensembl)
SCO2 ProteinO43819 (Uniprot-TrEMBL)
SCO2ProteinO43819 (Uniprot-TrEMBL)
SESN1 Gene ProteinENSG00000080546 (Ensembl)
SESN1,2,3 GenesComplexR-HSA-5629150 (Reactome)
SESN1,2,3:HOOS-C52-PRDX1 dimerComplexR-HSA-5631902 (Reactome)
SESN1,2,3:p-AMPK heterotrimer:AMPComplexR-HSA-5631939 (Reactome)
SESN1,2,3ComplexR-HSA-5629191 (Reactome)
SESN1-1,SESN1-3 R-HSA-5629186 (Reactome)
SESN2 Gene ProteinENSG00000130766 (Ensembl)
SESN2 ProteinP58004 (Uniprot-TrEMBL)
SESN3 Gene ProteinENSG00000149212 (Ensembl)
SESN3 ProteinP58005 (Uniprot-TrEMBL)
SFN ProteinP31947 (Uniprot-TrEMBL)
SLC38A9 ProteinQ8NBW4 (Uniprot-TrEMBL)
SURF1 ProteinQ15526 (Uniprot-TrEMBL)
TACO1 ProteinQ9BSH4 (Uniprot-TrEMBL)
TIGAR Gene ProteinENSG00000078237 (Ensembl)
TIGAR GeneGeneProductENSG00000078237 (Ensembl)
TIGARProteinQ9NQ88 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TNXRD1:FAD dimerComplexR-HSA-73532 (Reactome)
TP53

Tetramer:SESN1,2,3

Genes
ComplexR-HSA-5629180 (Reactome)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Tetramer:GLS2 GeneComplexR-HSA-5632919 (Reactome)
TP53 Tetramer:PTEN GeneComplexR-HSA-5632941 (Reactome)
TP53 Tetramer:RRM2B GeneComplexR-HSA-5632886 (Reactome)
TP53 Tetramer:SCO2 GeneComplexR-HSA-5632755 (Reactome)
TP53 Tetramer:TIGAR GeneComplexR-HSA-5628900 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
TP63 ProteinQ9H3D4 (Uniprot-TrEMBL)
TP63 Tetramer/ TP53 TetramerComplexR-HSA-5632387 (Reactome)
TP63/T53:DDIT4 GeneComplexR-HSA-5632392 (Reactome)
TSC1 ProteinQ92574 (Uniprot-TrEMBL)
TSC1:TSC2ComplexR-HSA-165175 (Reactome)
TSC1:p-S1387-TSC2ComplexR-HSA-381855 (Reactome)
TSC1ProteinQ92574 (Uniprot-TrEMBL)
TSC2 ProteinP49815 (Uniprot-TrEMBL)
TSC2ProteinP49815 (Uniprot-TrEMBL)
TXNProteinP10599 (Uniprot-TrEMBL)
TXNRD1 ProteinQ16881 (Uniprot-TrEMBL)
YWHAB ProteinP31946 (Uniprot-TrEMBL)
YWHAE ProteinP62258 (Uniprot-TrEMBL)
YWHAG ProteinP61981 (Uniprot-TrEMBL)
YWHAH ProteinQ04917 (Uniprot-TrEMBL)
YWHAQ ProteinP27348 (Uniprot-TrEMBL)
YWHAZ ProteinP63104 (Uniprot-TrEMBL)
ferriheme MetaboliteCHEBI:38574 (ChEBI)
ferroheme MetaboliteCHEBI:38573 (ChEBI)
mTORC1:Ragulator:Rag:GNP:RHEB:GDPComplexR-HSA-5693447 (Reactome)
miR-26A RISCComplexR-HSA-2318737 (Reactome)
miR-26A1 ProteinMI0000083 (miRBase mature sequence)
miR-26A2 ProteinMI0000750 (miRBase mature sequence)
p-AMPK heterotrimer:AMPComplexR-HSA-380931 (Reactome)
p-S1387-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S939,T1462-TSC2 ProteinP49815 (Uniprot-TrEMBL)
p-S939,T1462-TSC2:14-3-3 dimerComplexR-HSA-5632727 (Reactome)
p-S939,T1462-TSC2ProteinP49815 (Uniprot-TrEMBL)
p-T,p-S-AKTComplexR-HSA-202074 (Reactome)
p-T172-PRKAA2 ProteinP54646 (Uniprot-TrEMBL)
p-T174-PRKAA1 ProteinQ13131 (Uniprot-TrEMBL)
p-T305,S472-AKT3 ProteinQ9Y243 (Uniprot-TrEMBL)
p-T308,S473-AKT1 ProteinP31749 (Uniprot-TrEMBL)
p-T309,S474-AKT2 ProteinP31751 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
14-3-3 dimerR-HSA-5632732 (Reactome)
14-3-3 dimerR-HSA-5632738 (Reactome)
2xHC-TXNArrowR-HSA-3341343 (Reactome)
2xHC-TXNR-HSA-73646 (Reactome)
ADPArrowR-HSA-198609 (Reactome)
ADPArrowR-HSA-380927 (Reactome)
ATPR-HSA-198609 (Reactome)
ATPR-HSA-380927 (Reactome)
Active mTORC1 complexR-HSA-380979 (Reactome)
Active mTORC1 complexmim-catalysisR-HSA-380979 (Reactome)
COX ancilliary proteinsArrowR-HSA-163214 (Reactome)
COX11,14,16,18,20ArrowR-HSA-163214 (Reactome)
COX19ArrowR-HSA-163214 (Reactome)
Cytochrome c (oxidised)ArrowR-HSA-163214 (Reactome)
Cytochrome c (reduced)R-HSA-163214 (Reactome)
Cytochrome c oxidasemim-catalysisR-HSA-163214 (Reactome)
D-Fructose 2,6-bisphosphateR-HSA-5628905 (Reactome)
D-Glucono-1,5-lactone 6-phosphateArrowR-HSA-70377 (Reactome)
DDIT4 GeneR-HSA-5632386 (Reactome)
DDIT4 GeneR-HSA-5632393 (Reactome)
DDIT4:14-3-3 dimerArrowR-HSA-5632738 (Reactome)
DDIT4:14-3-3 dimerTBarR-HSA-5632732 (Reactome)
DDIT4ArrowR-HSA-5632386 (Reactome)
DDIT4R-HSA-5632738 (Reactome)
Fru(6)PArrowR-HSA-5628905 (Reactome)
Fru(6)PR-HSA-70475 (Reactome)
G6PArrowR-HSA-70475 (Reactome)
G6PD dimer and tetramermim-catalysisR-HSA-70377 (Reactome)
G6PR-HSA-70377 (Reactome)
GLS dimersmim-catalysisR-HSA-70609 (Reactome)
GLS2 GeneR-HSA-5632914 (Reactome)
GLS2 GeneR-HSA-5632924 (Reactome)
GLS2 dimerArrowR-HSA-5632924 (Reactome)
GPI dimermim-catalysisR-HSA-70475 (Reactome)
GPX2 tetramermim-catalysisR-HSA-3341277 (Reactome)
GSHArrowR-HSA-71682 (Reactome)
GSHR-HSA-3341277 (Reactome)
GSR-2:FAD dimermim-catalysisR-HSA-71682 (Reactome)
GSSGArrowR-HSA-3341277 (Reactome)
GSSGR-HSA-71682 (Reactome)
H+ArrowR-HSA-163214 (Reactome)
H+ArrowR-HSA-70377 (Reactome)
H+R-HSA-163214 (Reactome)
H+R-HSA-71682 (Reactome)
H+R-HSA-73646 (Reactome)
H2O2R-HSA-3341277 (Reactome)
H2O2R-HSA-3341343 (Reactome)
H2O2R-HSA-5631885 (Reactome)
H2OArrowR-HSA-163214 (Reactome)
H2OArrowR-HSA-3341277 (Reactome)
H2OArrowR-HSA-3341343 (Reactome)
H2OArrowR-HSA-5631885 (Reactome)
H2OR-HSA-5628905 (Reactome)
H2OR-HSA-70609 (Reactome)
HOOS-C52-PRDX1 dimerArrowR-HSA-5631885 (Reactome)
HOOS-C52-PRDX1 dimerR-HSA-5631903 (Reactome)
L-GlnR-HSA-70609 (Reactome)
L-GluArrowR-HSA-70609 (Reactome)
NADP+ArrowR-HSA-71682 (Reactome)
NADP+ArrowR-HSA-73646 (Reactome)
NADP+R-HSA-70377 (Reactome)
NADPHArrowR-HSA-70377 (Reactome)
NADPHR-HSA-71682 (Reactome)
NADPHR-HSA-73646 (Reactome)
NH4+ArrowR-HSA-70609 (Reactome)
O2R-HSA-163214 (Reactome)
PRDX1 dimerR-HSA-5631885 (Reactome)
PRDX1 dimermim-catalysisR-HSA-5631885 (Reactome)
PRDX1,2,5mim-catalysisR-HSA-3341343 (Reactome)
PTEN geneR-HSA-5632939 (Reactome)
PTEN geneR-HSA-5632993 (Reactome)
PTEN mRNA:miR-26A RISCArrowR-HSA-2318752 (Reactome)
PTEN mRNA:miR-26A RISCTBarR-HSA-2321904 (Reactome)
PTEN mRNAArrowR-HSA-5632993 (Reactome)
PTEN mRNAR-HSA-2318752 (Reactome)
PTEN mRNAR-HSA-2321904 (Reactome)
PTENArrowR-HSA-2321904 (Reactome)
PiArrowR-HSA-380979 (Reactome)
PiArrowR-HSA-5628905 (Reactome)
R-HSA-163214 (Reactome) Complex IV (COX, cytochrome c oxidase) contains the hemeprotein cytochrome a and a3. It also contains copper atoms which undergo a transition from Cu+ to Cu2+ during the transfer of electrons through the complex to molecular oxygen. A bimetallic centre containing a copper atom and a heme-linked iron protein binds oxygen after 4 electrons have been picked up. Water, the final product of oxygen reduction, is then released. Oxygen is the final electron acceptor in the respiratory chain. The overall reaction can be summed as

4Cyt c (red.) + 12H+ (in) + O2 = 4Cyt c (ox.) + 2H2O + 8H+ (out)

Four protons are taken up from the matrix side of the membrane to form the water (scalar protons). Wikstrom (1977) suggests 4 protons are additionally transferred out from the matrix to the intermembrane space.

COX ancillary proteins mediate membrane insertion, catalytic core processing, copper transport and insertion into core subunits and heme A biosynthesis (Stilburek et al. 2006, Fontanesi et al. 2006, Soto et al. 2012). To date, all Mendelian disorders presenting COX deficiency have been assigned to mutations in ancillary factors, with the exception of an infantile encephalomyopathy caused by a defective COX6B1 and an exocrine pancreatic insufficiency caused by a defective COX4I2 gene (Soto et al. 2012). Balsa et al have shown that NDUFA4, formerly considered to be a constituent of NADH dehydrogenase (Complex I), is instead a component of the cytochrome c oxidase (CIV) (Balsa et al. 2012). Patients with NDUFA4 mutations display COX deficiencies (Pitceathly et al. 2013).
R-HSA-165179 (Reactome) A membrane-associated TSC1 (hamartin) binds TSC2 (tuberin) and recruits it to the plasma membrane where it can exert its function as a GAP (GTPase activating protein) for the small GTPase RHEB (Cai et al. 2006).
R-HSA-198609 (Reactome) AKT phosphorylates and inhibits TSC2 (tuberin), a suppressor of the TOR kinase pathway, which senses nutrient levels in the environment. TSC2 forms a protein complex with TSC1 and this complex acts as a GAP (GTPase activating protein) for the RHEB G-protein. RHEB, in turn, activates the TOR kinase. Thus, an active AKT1 activates the TOR kinase, both of which are positive signals for cell growth (an increase in cell mass) and division.
The TOR kinase regulates two major processes: translation of selected mRNAs in the cell and autophagy. In the presence of high nutrient levels TOR is active and phosphorylates the 4EBP protein releasing the eukaryotic initiation factor 4E (eIF4E), which is essential for cap-dependent initiation of translation and promoting growth of the cell (PMID: 15314020). TOR also phosphorylates the S6 kinase, which is implicated in ribosome biogenesis as well as in the modification of the S6 ribosomal protein. AKT can also activate mTOR by another mechanism, involving phosphorylation of PRAS40, an inhibitor of mTOR activity.
R-HSA-2318752 (Reactome) MIR26A microRNAs, miR-26A1 and miR-26A2, transcribed from genes on chromosome 3 and 12, respectively, bind PTEN mRNA (Huse et al. 2009).

The MIR26A2 locus is frequently amplified in glioma tumors that retain one wild-type PTEN allele. The resulting miR-26A2 overexpression leads to down-regulation of PTEN protein level. Overexpression of miR-26A2 was shown to enhance tumorigenesis and negatively correlates with the loss of heterozygosity at the PTEN locus in a mouse PTEN +/- glioma model, based on monoallelic PTEN loss (Huse et al. 2009, Kim et al. 2010).
R-HSA-2321904 (Reactome) PTEN protein synthesis is negatively regulated by microRNAs miR-26A1 and miR-26A2, which recruit the RISC complex to PTEN mRNA. Overexpression of miR-26A2, caused by genomic amplification of MIR26A2 locus on chromosome 12, is frequently observed in human brain glioma tumors possessing one wild-type PTEN allele, and is thought to contribute to tumor progression by repressing PTEN protein expression from the remaining allele (Huse et al. 2009). Other microRNAs, which may also be altered in cancer, such as miR-17, miR-19a, miR-19b, miR-20a, miR-20b, miR-21, miR-22, miR-25, miR-93, miR-106a, miR-106b, miR 205, and miR 214, also bind PTEN mRNA and inhibit its translation into protein (Meng et al. 2007, Xiao et al. 2008, Yang et al. 2008, Kim et al. 2010, Poliseno, Salmena, Riccardi et al. 2010, Zhang et al. 2010, Tay et al. 2011, Qu et al. 2012, Cai et al. 2013).
R-HSA-3341277 (Reactome) GPX2 (located in the gastrointestinal tract, also called GSHPx-GI, GPX-GI, and GI-GPx), like glutathione peroxidase 1 (GPX1, ubiquitous), reduces one molecule of hydrogen peroxide (H2O2) with two molecules of glutathione to yield one molecule of oxidized glutathione (glutathione disulfide, GSSG) and two molecules of water (Chu et al. 1998).
R-HSA-3341343 (Reactome) Peroxiredoxin 1 (PRDX1), PRDX2, and PRDX5 in the cytosol reduce hydrogen peroxide (H2O2) with thioredoxin yielding oxidized thioredoxin and water (Yamashita et al. 1999, Lee et al. 2007, Nagy et al. 2011).
R-HSA-380927 (Reactome) Activated AMPK (phosphorylated on the alpha subunit and with AMP bound) phosphorylates TSC2 (also known as tuberin) on Ser-1387, thereby activating the GTPase activating protein (GAP) activity of the Tuberous Sclerosis Complex (TSC). The TSC tumor suppressor is a critical upstream inhibitor of the mTORC1 complex. TSC is a GTPase-activating protein that stimulates the intrinsic GTPase activity of the small G-protein Rheb. This inactivates Rheb by stimulating its GTPase activity. The GDP-bound form of Rheb looses the ability to activate the kinase activity of the mTORC1 complex (Sancak et al. 2007). Loss of TSC1 or TSC2 leads to hyperactivation of mTORC1.

Phosphorylation of TSC1 and TSC2 serves as an integration point for a wide variety of environmental signals that regulate mTORC1 (Sabatini 2006). Mitogen-activated kinases including Akt, Erk, and Rsk directly phosphorylate TSC2, leading to its inactivation by an unknown mechanism. Another Akt substrate, PRAS40, was recently shown to bind and inhibit the mTORC1 complex. Upon phosphorylation by Akt, PRAS40 no longer inhibits mTORC1 (Sancak et al. 2007; Vander Haar et al. 2007).
R-HSA-380979 (Reactome) TSC2 (in the TSC complex) functions as a GTPase-activating protein and stimulates the intrinsic GTPase activity of the small G-protein Rheb. This results in the conversion of Rheb:GTP to Rheb:GDP. GDP-bound Rheb is unable to activate mTOR (Inoki et al. 2003, Tee et al. 2003). It is not demonstrated that RHEB hydrolyzes GTP when present in the mTORC1 complex; given the low affinity of RHEB for mTOR, it may dissociate from the mTORC1 complex before TSC2 stimulates hydrolysis of GTP; TSC2 may not have access to critical residues of RHEB when present inside mTORC1.
R-HSA-5628899 (Reactome) TIGAR gene possesses two TP53 (p53) binding sites, one upstream of the first exon and another within the first intron. TP53 can bind both sites, with a higher affinity for the intronic site (Bensaad et al. 2006).
R-HSA-5628901 (Reactome) TIGAR was first identified as a TP53 target through high-throughput gene expression profiling (Jen and Cheung 2005). TP53 stimulates TIGAR transcription, although TIGAR can be regulated through TP53-independent mechanisms, including TP53 family members TP63 (p63) and TP73 (p73). TIGAR is induced by TP53 under low stress levels and decreases under high stress levels (Bensaad et al. 2006). TIGAR functions as a fructose-2,6-bisphosphatase, thereby lowering glycolytic flux and promoting antioxidant functions. By protecting cells from oxidative stress, TIGAR may mediate some of the tumor suppressor activity of p53 but could also contribute to tumorigenesis. (Bensaad, 2006, Lee et al. 2014).
R-HSA-5628905 (Reactome) TIGAR shares similarity with PGMs (phosphoglycerate mutases), especially PFK2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase). TIGAR possesses only the bisphosphatase domain and converts D-fructose 2,6-bisphosphate into D-fructose 6-phosphate (Bensaad et al. 2006). Reduction of fructose 2,6-bisphosphate levels correlates with decrease in glycolytic rates, which makes cells more sensitive to apoptotic stimuli (Vander Heiden et al. 2001). Alternatively, fructose 6-phosphate can be isomerized to glucose 6-phosphate, which is diverted to the pentose phosphate pathway, which can have an anti-apoptotic effect (Boada et al. 2000, Perez et al. 2000). In the pentose phosphate pathway, oxidized glutathione is reduced, and this reduced glutathione can then be used by glutathione peroxidase to remove hydrogen peroxide, thereby protecting cells from the oxidative stress (Kletzien et al. 1994, Fico et al. 2004, Tian et al. 1999). Indeed, expression of TIGAR increases reduced glutathione to oxidized glutathione ratio and lowers ROS (reactive oxygen species) levels in cells (Bensaad et al. 2006, Lee et al. 2014).
R-HSA-5629187 (Reactome) TP53 (p53) binds to the p53 response element in the intron 2 of SESN1 gene and stimulates transcription of SESN1 transcripts SESN1-1 and SESN1-3, also known as PA26 T2 and PA26 T3 (Velasco-Miguel et al. 1999). Recently, TP53 binding to SESN2 gene regulatory elements has been identified by ChIPseq (Menendez et al. 2013), and SESN2 gene expression was previously shown to be responsive to TP53 (Budanov et al. 2002). Rat ortholog of SESN3 was shown to possess p53 binding sites in the promoter region, but direct binding of TP53 to regulatory elements of human SESN3 has not been examined (Brynczka et al. 2007).
R-HSA-5629189 (Reactome) Sestrins (SESN) are a small family of stress-sensitive gene that are conserved across several species. Mammals express three different SESN family members characterized as SESN1-3. Sestrin genes, SESN1, SESN2 and SESN3, are upregulated in response to TP53-mediated transcriptional regulation. SESN1 and SESN2 were classified as members of the growth arrest and DNA damage (GADD) gene family that can regulate cell growth and viability under different cellular pressures. In particular, p53 negatively modulates the mTOR pahtway via SESN1 and SESN2 upregulation (Feng 2010). SESN3 was identified shortly after SESN2 through in silico analysis and was found to be a target of the forkhead transcription factor (FOXO) family. A specific TP53 binding site on the human SESN3 promoter has not been identified yet, but was found in the rat ortholog (Velasco-Miguel et al. 1999, Budanov et al. 2002, Brynczka et al. 2007).
R-HSA-5631885 (Reactome) The activity of eukaryotic PRDX1 gradually decreases with time, which is due to the overoxidation of the catalytic cysteine C52. Normally, oxidized cysteine C52-SOH is generated as a catalytic intermediate, which is subsequently reduced by thioredoxin. Occasionally, further oxidation happens, generating C52-SOOH , where the catalytic cysteine is converted to cysteine-sulfinic acid. This over-oxidation cannot be reversed by thioredoxin (Yang et al. 2002, Budanov et al. 2004). Bacterial peroxiredoxin AhpC does not undergo over-oxidation due to structural difference (Wood et al. 2003).
R-HSA-5631903 (Reactome) Sestrins (SESN1, SESN2 and likely SESN3) bind overoxidized PRDX1, in which the catalytic cysteine C52 has been converted to cysteine-sulfinic acid. Among all peroxiredoxins, PRDX1 is the most abundant member of the PRDX family. The major function is to protect cells against reactive oxygen species (ROS), thus impacting on cell proliferation and survival (Gong et al. 2015). While several reports state that sestrins reduce overoxidized PRDX1 to the catalytically active homodimer (Budanov et al. 2004, Papadia et al. 2008, Essler et al. 2009), there are conflicting reports claiming that sestrins do not possess cysteine sulfinyl reductase activity (Woo et al. 2009).
R-HSA-5631941 (Reactome) SESN1, SESN2 and possibly SESN3 are able to bind the AMPK complex and increase its catalytic activity. The exact mechanism has not been elucidated, but recent studies suggest that sestrin-bound AMPK is resistant to inactivation through AKT-induced dephosphorylation (Budanov and Karin 2008, Sanli et al. 2012, Cam et al. 2014).
R-HSA-5632386 (Reactome) Transcription of DDIT4 (REDD1) gene is stimulated by TP63, both during mouse embryonal development and under conditions of genotoxic and oxidative stress. TP53 stimulates DDIT4 transcription after TP53 activation by ionizing radiation, but it seems that TP63 is the main activator of DDIT4 transcription under stress conditions (Ellisen et al. 2002).
R-HSA-5632393 (Reactome) DDIT4 (REDD1) gene has a p53 response element immediately upstream of the transcription start site, and this p53 response element is able to bind both TP63 and TP53 transcription factors (Ellisen et al. 2002).
R-HSA-5632732 (Reactome) Phosphorylation of TSC2 by AKT enables association of TSC2 with 14-3-3 proteins YWHAB (14-3-3 protein beta/alpha), YWHAQ (14-3-3 protein theta), YWHAG (14-3-3 protein gamma), YWHAH (14-3-3 protein eta), YWHAE (14-3-3 protein epsilon), YWHAZ (14-3-3 protein zeta/delta) or SFN (14-3-3 protein sigma) (Liu et al. 2002). Binding to 14-3-3 proteins sequesters TSC2 to the cytosol and prevents its association with TSC1 (Cai et al. 2006).
R-HSA-5632738 (Reactome) DDIT4 (REDD1) binds 14-3-3 proteins through a conserved 14-3-3 binding motif Arg-X-X-X-Ser/Thr-X-Pro (DeYoung et al. 2008). Binding of DDIT4 to 14-3-3 proteins competes with 14-3-3 binding to TSC2 and thus prevents AKT-mediated inactivation of TSC2 (Cam et al. 2014).
R-HSA-5632759 (Reactome) TP53 (p53) binds the p53 response element in the intron 1 of SCO2 (Synthesis of Cytochrome c Oxidase 2) gene (Matoba et al. 2006). The binding of TP53 on SCO2 gene was verified in a genome wide chromatin immunoprecipitation study (Wei et al. 2006). Tp53 was also found to bind to the promoter region in mouse Sco2 gene to stimulate its expression in response to physical exercise (Qi et al. 2011).
R-HSA-5632766 (Reactome) TP53 (p53) directly stimulates transcription of the SCO2 gene. SCO2, synthesis of cytochrome c oxidase 2, is a copper-binding assembly protein for the mitochondrial COX (cytochrome C oxidase) complex which enables aerobic respiration. When SCO2 levels are reduced, as occurs in TP53 deficient cells, the glycolysis becomes the main energy source for the cell. The TP53-mediated regulation of SCO2 and other mitochondrial biogenesis genes provides a possible explanation for the Warburg effect (Warburg 1956) observed in some cancer cells (Matoba et al. 2006).
R-HSA-5632887 (Reactome) TP53 (p53) binds the p53-binding site in the first intron of RRM2B (p53R2) gene, which encodes a subunit of the ribonucleotide reductase complex (Tanaka et al. 2000). RRM2B is also regulated by TP73 (p73), a p53 family member (Nakano et al. 2000).
R-HSA-5632892 (Reactome) TP53 (p53) directly stimulates transcription of RRM2B gene (p53R2), which encodes a critical subunit of the ribonucleotide reductase complex (Tanaka et al. 2000), responsible for de novo conversion of ribonucleotides (NTPs) to deoxyribonucleotides (dNTPs). This regulation provides a direct mechanism through which TP53 contributes to DNA synthesis/repair. Mutations in RRM2B gene cause severe mitochondrial DNA depletion (Bourdon et al. 2007, Kulawiec et al. 2009).
R-HSA-5632914 (Reactome) The mitochondrial glutaminase GLS2 gene possesses two putative p53-binding sites in its promoter and one putative p53 binding site in the first intron. TP53 was demonstrated to bind to p53-response elements in the promoter but not intron 1 of GLS2 (Hu et al. 2010, Suzuki et al. 2010).
R-HSA-5632924 (Reactome) TP53 (p53) directly stimulates transcription of mitochondrial glutaminase GLS2 under non-stress and stress conditions. Increased GLS2 levels lead to increased production of glutamate and alpha-ketoglutarate, increased mitochondrial respiration rate, and reduced ROS (reactive oxygen species) load through enhanced glutathione reduction (Hu et al. 2010).

Elevated GLS2 was associated with lower levels of intracellular ROS and a decrease in DNA oxidation. GLS2 knockdown resulted in higher ROS levels and was associated with stimulation of p53-induced cell death (Suzuki et al. 2010).

R-HSA-5632939 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) binds to the p53-binding site at the PTEN promoter level (Stambolic et al. 2001).
R-HSA-5632993 (Reactome) PTEN (phosphatase and tensin homolog deleted in chromosome 10) is a tumor suppressor gene that is deleted or mutated in a variety of human cancers. TP53 (p53) stimulates PTEN transcription (Stambolic et al. 2000, Singh et al. 2002). PTEN, acting as a negative regulator of PI3K/AKT signaling, affects cell survival, cell cycling, proliferation and migration. PTEN regulates TP53 stability by inhibiting AKT-mediated activation of TP53 ubiquitin ligase MDM2, and thus enhances TP53 transcriptional activity and its own transcriptional activation by TP53. Beside their cross-regulation, PTEN and TP53 can interact and cooperate to regulate survival or apoptotic phenomena (Stambolic et al. 2000, Singh et al. 2002, Nakanishi et a