TP53 (p53) tumor suppressor protein is a transcription factor that functions as a homotetramer (Jeffrey et al. 1995). The protein levels of TP53 are low in unstressed cells due to MDM2-mediated ubiquitination that triggers proteasome-mediated degradation of TP53 (Wu et al. 1993). The E3 ubiquitin ligase MDM2 functions as a homodimer/homo-oligomer or a heterodimer/hetero-oligomer with MDM4 (MDMX) (Linares et al. 2003, Toledo and Wahl 2007, Cheng et al. 2011, Wade et al. 2013).
Activating phosphorylation of TP53 at serine residues S15 and S20 in response to genotoxic stress disrupts TP53 interaction with MDM2. In contrast to MDM2, E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate phosphorylated TP53 (Yang et al. 2007). Binding of MDM2 to TP53 is also inhibited by the tumor suppressor p14-ARF, transcribed from the CDKN2A gene in response to oncogenic signaling or oxidative stress (Zhang et al. 1998, Parisi et al. 2002, Voncken et al. 2005). Ubiquitin-dependant degradation of TP53 can also be promoted by PIRH2 (Leng et al. 2003) and COP1 (Dornan et al. 2004) ubiquitin ligases. HAUSP (USP7) can deubiquitinate TP53, contributing to TP53 stabilization (Li et al. 2002).<p>While post-translational regulation plays a prominent role, TP53 activity is also controlled at the level of promoter function (reviewed in Saldana-Meyer and Recillas-Targa 2011), mRNA stability and translation efficiency (Mahmoudi et al. 2009, Le et al. 2009, Takagi et al. 2005).
View original pathway at:Reactome.</div>
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Mayo LD, Donner DB.; ''A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus.''; PubMedEurope PMCScholia
Gully CP, Velazquez-Torres G, Shin JH, Fuentes-Mattei E, Wang E, Carlock C, Chen J, Rothenberg D, Adams HP, Choi HH, Guma S, Phan L, Chou PC, Su CH, Zhang F, Chen JS, Yang TY, Yeung SC, Lee MH.; ''Aurora B kinase phosphorylates and instigates degradation of p53.''; PubMedEurope PMCScholia
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Parisi T, Pollice A, Di Cristofano A, Calabrò V, La Mantia G.; ''Transcriptional regulation of the human tumor suppressor p14(ARF) by E2F1, E2F2, E2F3, and Sp1-like factors.''; PubMedEurope PMCScholia
Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, Taya Y, Prives C, Abraham RT.; ''A role for ATR in the DNA damage-induced phosphorylation of p53.''; PubMedEurope PMCScholia
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Chen J, Marechal V, Levine AJ.; ''Mapping of the p53 and mdm-2 interaction domains.''; PubMedEurope PMCScholia
Keller DM, Lu H.; ''p53 serine 392 phosphorylation increases after UV through induction of the assembly of the CK2.hSPT16.SSRP1 complex.''; PubMedEurope PMCScholia
Meulmeester E, Maurice MM, Boutell C, Teunisse AF, Ovaa H, Abraham TE, Dirks RW, Jochemsen AG.; ''Loss of HAUSP-mediated deubiquitination contributes to DNA damage-induced destabilization of Hdmx and Hdm2.''; PubMedEurope PMCScholia
Waterman JL, Shenk JL, Halazonetis TD.; ''The dihedral symmetry of the p53 tetramerization domain mandates a conformational switch upon DNA binding.''; PubMedEurope PMCScholia
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Li M, Brooks CL, Kon N, Gu W.; ''A dynamic role of HAUSP in the p53-Mdm2 pathway.''; PubMedEurope PMCScholia
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Shieh SY, Ahn J, Tamai K, Taya Y, Prives C.; ''The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites.''; PubMedEurope PMCScholia
Linares LK, Hengstermann A, Ciechanover A, Müller S, Scheffner M.; ''HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53.''; PubMedEurope PMCScholia
Endo Y, Fujita T, Tamura K, Tsuruga H, Nojima H.; ''Structure and chromosomal assignment of the human cyclin G gene.''; PubMedEurope PMCScholia
Lyo D, Xu L, Foster DA.; ''Phospholipase D stabilizes HDM2 through an mTORC2/SGK1 pathway.''; PubMedEurope PMCScholia
Fang S, Jensen JP, Ludwig RL, Vousden KH, Weissman AM.; ''Mdm2 is a RING finger-dependent ubiquitin protein ligase for itself and p53.''; PubMedEurope PMCScholia
Cheng Q, Cross B, Li B, Chen L, Li Z, Chen J.; ''Regulation of MDM2 E3 ligase activity by phosphorylation after DNA damage.''; PubMedEurope PMCScholia
Luciani MG, Hutchins JR, Zheleva D, Hupp TR.; ''The C-terminal regulatory domain of p53 contains a functional docking site for cyclin A.''; PubMedEurope PMCScholia
Zauberman A, Lupo A, Oren M.; ''Identification of p53 target genes through immune selection of genomic DNA: the cyclin G gene contains two distinct p53 binding sites.''; PubMedEurope PMCScholia
D'Orazi G, Cecchinelli B, Bruno T, Manni I, Higashimoto Y, Saito S, Gostissa M, Coen S, Marchetti A, Del Sal G, Piaggio G, Fanciulli M, Appella E, Soddu S.; ''Homeodomain-interacting protein kinase-2 phosphorylates p53 at Ser 46 and mediates apoptosis.''; PubMedEurope PMCScholia
Taira N, Yamamoto H, Yamaguchi T, Miki Y, Yoshida K.; ''ATM augments nuclear stabilization of DYRK2 by inhibiting MDM2 in the apoptotic response to DNA damage.''; PubMedEurope PMCScholia
Takagi M, Absalon MJ, McLure KG, Kastan MB.; ''Regulation of p53 translation and induction after DNA damage by ribosomal protein L26 and nucleolin.''; PubMedEurope PMCScholia
Taira N, Nihira K, Yamaguchi T, Miki Y, Yoshida K.; ''DYRK2 is targeted to the nucleus and controls p53 via Ser46 phosphorylation in the apoptotic response to DNA damage.''; PubMedEurope PMCScholia
Stenger JE, Tegtmeyer P, Mayr GA, Reed M, Wang Y, Wang P, Hough PV, Mastrangelo IA.; ''p53 oligomerization and DNA looping are linked with transcriptional activation.''; PubMedEurope PMCScholia
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Katayama H, Sasai K, Kawai H, Yuan ZM, Bondaruk J, Suzuki F, Fujii S, Arlinghaus RB, Czerniak BA, Sen S.; ''Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53.''; PubMedEurope PMCScholia
Ciccia A, Elledge SJ.; ''The DNA damage response: making it safe to play with knives.''; PubMedEurope PMCScholia
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Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG, Zuo Y, Kawai H, Shadfan M, Ganapathy S, Yuan ZM.; ''The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo.''; PubMedEurope PMCScholia
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Momand J, Zambetti GP, Olson DC, George D, Levine AJ.; ''The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation.''; PubMedEurope PMCScholia
Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B.; ''Amplification of a gene encoding a p53-associated protein in human sarcomas.''; PubMedEurope PMCScholia
Pant V, Xiong S, Iwakuma T, Quintás-Cardama A, Lozano G.; ''Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability.''; PubMedEurope PMCScholia
Okamoto K, Li H, Jensen MR, Zhang T, Taya Y, Thorgeirsson SS, Prives C.; ''Cyclin G recruits PP2A to dephosphorylate Mdm2.''; PubMedEurope PMCScholia
Milne D, Kampanis P, Nicol S, Dias S, Campbell DG, Fuller-Pace F, Meek D.; ''A novel site of AKT-mediated phosphorylation in the human MDM2 onco-protein.''; PubMedEurope PMCScholia
Lu M, Wang J, Jones KT, Ives HE, Feldman ME, Yao LJ, Shokat KM, Ashrafi K, Pearce D.; ''mTOR complex-2 activates ENaC by phosphorylating SGK1.''; PubMedEurope PMCScholia
Zhou BP, Liao Y, Xia W, Zou Y, Spohn B, Hung MC.; ''HER-2/neu induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation.''; PubMedEurope PMCScholia
Cheng Q, Chen L, Li Z, Lane WS, Chen J.; ''ATM activates p53 by regulating MDM2 oligomerization and E3 processivity.''; PubMedEurope PMCScholia
Boyd SD, Tsai KY, Jacks T.; ''An intact HDM2 RING-finger domain is required for nuclear exclusion of p53.''; PubMedEurope PMCScholia
Lee JH, Jeong MW, Kim W, Choi YH, Kim KT.; ''Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress.''; PubMedEurope PMCScholia
Maki CG.; ''Oligomerization is required for p53 to be efficiently ubiquitinated by MDM2.''; PubMedEurope PMCScholia
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Khanna KK, Keating KE, Kozlov S, Scott S, Gatei M, Hobson K, Taya Y, Gabrielli B, Chan D, Lees-Miller SP, Lavin MF.; ''ATM associates with and phosphorylates p53: mapping the region of interaction.''; PubMedEurope PMCScholia
Zhang J, Krishnamurthy PK, Johnson GV.; ''Cdk5 phosphorylates p53 and regulates its activity.''; PubMedEurope PMCScholia
Xie S, Wang Q, Wu H, Cogswell J, Lu L, Jhanwar-Uniyal M, Dai W.; ''Reactive oxygen species-induced phosphorylation of p53 on serine 20 is mediated in part by polo-like kinase-3.''; PubMedEurope PMCScholia
Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y.; ''Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway.''; PubMedEurope PMCScholia
Stevenson LF, Sparks A, Allende-Vega N, Xirodimas DP, Lane DP, Saville MK.; ''The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2.''; PubMedEurope PMCScholia
Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H.; ''A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1.''; PubMedEurope PMCScholia
Chehab NH, Malikzay A, Stavridi ES, Halazonetis TD.; ''Phosphorylation of Ser-20 mediates stabilization of human p53 in response to DNA damage.''; PubMedEurope PMCScholia
Jeffrey PD, Gorina S, Pavletich NP.; ''Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms.''; PubMedEurope PMCScholia
García-Martínez JM, Alessi DR.; ''mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1).''; PubMedEurope PMCScholia
Wu L, Ma CA, Zhao Y, Jain A.; ''Aurora B interacts with NIR-p53, leading to p53 phosphorylation in its DNA-binding domain and subsequent functional suppression.''; PubMedEurope PMCScholia
Pereg Y, Shkedy D, de Graaf P, Meulmeester E, Edelson-Averbukh M, Salek M, Biton S, Teunisse AF, Lehmann WD, Jochemsen AG, Shiloh Y.; ''Phosphorylation of Hdmx mediates its Hdm2- and ATM-dependent degradation in response to DNA damage.''; PubMedEurope PMCScholia
Allende-Vega N, Sparks A, Lane DP, Saville MK.; ''MdmX is a substrate for the deubiquitinating enzyme USP2a.''; PubMedEurope PMCScholia
Yang W, Rozan LM, McDonald ER, Navaraj A, Liu JJ, Matthew EM, Wang W, Dicker DT, El-Deiry WS.; ''CARPs are ubiquitin ligases that promote MDM2-independent p53 and phospho-p53ser20 degradation.''; PubMedEurope PMCScholia
Pearce LR, Huang X, Boudeau J, Pawłowski R, Wullschleger S, Deak M, Ibrahim AF, Gourlay R, Magnuson MA, Alessi DR.; ''Identification of Protor as a novel Rictor-binding component of mTOR complex-2.''; PubMedEurope PMCScholia
Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V, Lodish HF, Lim B.; ''MicroRNA-125b is a novel negative regulator of p53.''; PubMedEurope PMCScholia
Canman CE, Lim DS, Cimprich KA, Taya Y, Tamai K, Sakaguchi K, Appella E, Kastan MB, Siliciano JD.; ''Activation of the ATM kinase by ionizing radiation and phosphorylation of p53.''; PubMedEurope PMCScholia
Chehab NH, Malikzay A, Appel M, Halazonetis TD.; ''Chk2/hCds1 functions as a DNA damage checkpoint in G(1) by stabilizing p53.''; PubMedEurope PMCScholia
Okamoto K, Beach D.; ''Cyclin G is a transcriptional target of the p53 tumor suppressor protein.''; PubMedEurope PMCScholia
Tomasini R, Samir AA, Carrier A, Isnardon D, Cecchinelli B, Soddu S, Malissen B, Dagorn JC, Iovanna JL, Dusetti NJ.; ''TP53INP1s and homeodomain-interacting protein kinase-2 (HIPK2) are partners in regulating p53 activity.''; PubMedEurope PMCScholia
Sarkari F, La Delfa A, Arrowsmith CH, Frappier L, Sheng Y, Saridakis V.; ''Further insight into substrate recognition by USP7: structural and biochemical analysis of the HdmX and Hdm2 interactions with USP7.''; PubMedEurope PMCScholia
Chen L, Gilkes DM, Pan Y, Lane WS, Chen J.; ''ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage.''; PubMedEurope PMCScholia
Li HH, Li AG, Sheppard HM, Liu X.; ''Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression.''; PubMedEurope PMCScholia
Woo SY, Kim DH, Jun CB, Kim YM, Haar EV, Lee SI, Hegg JW, Bandhakavi S, Griffin TJ, Kim DH.; ''PRR5, a novel component of mTOR complex 2, regulates platelet-derived growth factor receptor beta expression and signaling.''; PubMedEurope PMCScholia
Hofmann TG, Möller A, Sirma H, Zentgraf H, Taya Y, Dröge W, Will H, Schmitz ML.; ''Regulation of p53 activity by its interaction with homeodomain-interacting protein kinase-2.''; PubMedEurope PMCScholia
Kobayashi T, Cohen P.; ''Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2.''; PubMedEurope PMCScholia
Hirao A, Kong YY, Matsuoka S, Wakeham A, Ruland J, Yoshida H, Liu D, Elledge SJ, Mak TW.; ''DNA damage-induced activation of p53 by the checkpoint kinase Chk2.''; PubMedEurope PMCScholia
Mahmoudi S, Henriksson S, Corcoran M, Méndez-Vidal C, Wiman KG, Farnebo M.; ''Wrap53, a natural p53 antisense transcript required for p53 induction upon DNA damage.''; PubMedEurope PMCScholia
Amato R, D'Antona L, Porciatti G, Agosti V, Menniti M, Rinaldo C, Costa N, Bellacchio E, Mattarocci S, Fuiano G, Soddu S, Paggi MG, Lang F, Perrotti N.; ''Sgk1 activates MDM2-dependent p53 degradation and affects cell proliferation, survival, and differentiation.''; PubMedEurope PMCScholia
Saldaña-Meyer R, Recillas-Targa F.; ''Transcriptional and epigenetic regulation of the p53 tumor suppressor gene.''; PubMedEurope PMCScholia
Li M, Luo J, Brooks CL, Gu W.; ''Acetylation of p53 inhibits its ubiquitination by Mdm2.''; PubMedEurope PMCScholia
Hou X, Liu JE, Liu W, Liu CY, Liu ZY, Sun ZY.; ''A new role of NUAK1: directly phosphorylating p53 and regulating cell proliferation.''; PubMedEurope PMCScholia
Feng J, Tamaskovic R, Yang Z, Brazil DP, Merlo A, Hess D, Hemmings BA.; ''Stabilization of Mdm2 via decreased ubiquitination is mediated by protein kinase B/Akt-dependent phosphorylation.''; PubMedEurope PMCScholia
Lee JH, Kim HS, Lee SJ, Kim KT.; ''Stabilization and activation of p53 induced by Cdk5 contributes to neuronal cell death.''; PubMedEurope PMCScholia
Okamoto K, Kamibayashi C, Serrano M, Prives C, Mumby MC, Beach D.; ''p53-dependent association between cyclin G and the B' subunit of protein phosphatase 2A.''; PubMedEurope PMCScholia
Xie S, Wu H, Wang Q, Cogswell JP, Husain I, Conn C, Stambrook P, Jhanwar-Uniyal M, Dai W.; ''Plk3 functionally links DNA damage to cell cycle arrest and apoptosis at least in part via the p53 pathway.''; PubMedEurope PMCScholia
DNA double strand break (DSB) response involves sensing of DNA DSBs by the MRN complex which triggers ATM activation. ATM phosphorylates a number of proteins involved in DNA damage checkpoint signaling, as well as proteins directly involved in the repair of DNA DSBs. For a recent review, please refer to Ciccia and Elledge, 2010.
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.
Phosphorylation of TP53 (p53) at the N-terminal serine residues S15 and S20 plays a critical role in protein stabilization as phosphorylation at these sites interferes with binding of the ubiquitin ligase MDM2 to TP53. Several different kinases can phosphorylate TP53 at S15 and S20. In response to double strand DNA breaks, S15 is phosphorylated by ATM (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998), and S20 by CHEK2 (Chehab et al. 1999, Chehab et al. 2000, Hirao et al. 2000). DNA damage or other types of genotoxic stress, such as stalled replication forks, can trigger ATR-mediated phosphorylation of TP53 at S15 (Lakin et al. 1999, Tibbetts et al. 1999) and CHEK1-mediated phosphorylation of TP53 at S20 (Shieh et al. 2000). In response to various types of cell stress, NUAK1 (Hou et al. 2011), CDK5 (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008), AMPK (Jones et al. 2005) and TP53RK (Abe et al. 2001, Facchin et al. 2003) can phosphorylate TP53 at S15, while PLK3 (Xie, Wang et al. 2001, Xie, Wu et al. 2001) can phosphorylate TP53 at S20.
Phosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).
MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).
NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).
The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).
Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012).
AKT phosphorylates MDM2 on two serine residues, at positions 166 and 188 (Mayo and Donner 2001, Feng et al. 2004, Milne et al. 2004). AKT-mediated phosphorylation of the E3 ubiquitin-protein ligase MDM2 promotes nuclear localization and interferes with the interaction between MDM2 and p14-ARF, thereby decreasing p53 stability. This leads to a decreased expression of p53 target genes, such as BAX, that promote apoptosis (Zhou et al. 2001, Mayo and Donner 2001).
In the presence of DAXX, USP7 deubiquitinates MDM2. DAXX expression therefore prolongs MDM2 half-life and inhibits TP53 activation (Tang et al. 2006). In the absence of DAXX or when DNA damage response is activated (Tang et al. 2006), USP7 associates with ubiquitinated TP53 rather than ubiquitinated MDM2 (Li et al. 2004, Sheng et al. 2006, Hu et al. 2006). USP7 also deubiquitinates MDM4 (MDMX) (Meulmeester et al. 2005, Sarkari et al. 2010). The role of DAXX in deubiquitination of MDM4 has not been examined.
USP7 (HAUSP) can deubiquitinate TP53, thereby prolonging TP53 half-life and enhancing TP53 activity (Li et al. 2002, Li et al. 2004, Sheng et al. 2006, Hu et al. 2006).
CHEK2 (Chk2) kinase is required for phosphorylation of MDM4 at serine residues S342 and S367 in vivo. CHEK2-mediated phosphorylation stimulates MDM4 ubiquitination by MDM2 and subsequent degradation (Chen et al. 2005).
Human MDM4 (MDMX) is phosphorylated on serine residue S403 by ATM. This site is important for MDM2-mediated ubiquitination of MDM4 after induction of double strand DNA breaks (Pereg et al. 2005, Chen et al. 2005).
The N-terminal portion of MDM2 binds the N-terminal transactivation domain of TP53 (p53) and inhibits transcriptional transactivation by TP53 (Momand et al. 1992, Oliner et al. 1992, Oliner et al. 1993, Chen et al. 1993).
TP53 (p53) binds the p53 response element in the first intron of cyclin G1 (CCNG1) gene. An additional p53 response element may be located in the CCNG1 promoter (Okamoto and Beach 1994, Zauberman et al. 1995, Endo et al. 1996).
Upon binding to the p53 response elements in the promoter and/or the first intron of CCNG1 (cyclin G1) gene, TP53 induces CCNG1 transcription (Okamoto and Beach 1994, Zauberman et al. 1995, Endo et al. 1996).
The protein serine/threonine phosphatase complex PP2A, recruited to MDM2 through interaction of the PP2A regulatory subunit PPP2R5C and cyclin G1 (CCNG1) dephosphorylates MDM2 on threonine residue T218 (T218 in human MDM2 corresponds to T216 in mouse Mdm2). Dephosphorylation of T218 increases the affinity of MDM2 for TP53 (p53), leading to p53 down-regulation (Okamoto et al. 2002).
CCNG1-recruited PP2A can also dephosphorylate serine residue S166 of human MDM2 (Okamoto et al. 2002).
CCNG1 (cyclin G1) simultaneously interacts with the regulatory subunit of the PP2A protein phosphatase complex, PPP2R5C (Okamoto et al. 1996), and MDM2, thus recruiting the PP2A complex to MDM2 (Okamoto et al. 2002).
CDK1 or CDK2 in complex with CCNA (cyclin A) phosphorylates MDM2 at threonine residue T218. Phosphorylation of MDM2 at T218 increases its affinity for p14-ARF and reduces its affinity for TP53 (p53), thus resulting in TP53 upregulation (Zhang and Prives 2001).
AKT- or SGK1-phosphorylated MDM2 residues S166 and S188 are in the vicinity of the MDM2 nuclear localization signal. MDM2 phosphorylation by AKT or SGK1 leads to MDM2 translocation from the cytosol to the nucleus (Mayo and Donner 2001).
Upon MDM2-mediated ubiquitination, TP53 is exported from the nucleus to the cytosol. TP53 nuclear export requires the nuclear export sequence (NES) of TP53, but not the NES of MDM2 (Boyd et al. 2000. Geyer et al. 2000).
The TORC2 complex phosphorylates SGK1 at serine residue S422, located in the carboxy-terminal hydrophobic motif of SGK1. Phosphorylation at S422 contributes to SGK1 activation (Garcia-Martinez and Alessi 2008, Lu et al. 2010).
SGK1 phosphorylates MDM2 at serine residues S166 and S188, resulting in MDM2 activation (Amato et al. 2009, Lyo et al. 2010). SGK1 may play a more prominent role in MDM2 activation than AKT (Lyo et al. 2010).
PDPK1 (PDK1) activates SGK1 by phosphorylating threonine residue T256, located in the activation loop of SGK1. Phosphorylation of SGK1 at S422 facilitates subsequent phosphorylation at T256 (Kobayashi and Cohen 1999).
Binding of PRDM1 (BLIMP1) to the promoter region of the TP53 (p53) gene inhibits TP53 transcription (Yan et al. 2007) probably by inducing repressive methylation of the TP53 promoter (Weige et al. 2014).
E3 ubiquitin ligases RNF34 (CARP1) and RFFL (CARP2) can ubiquitinate TP53 (p53) phosphorylated at the N-terminus and target it for proteasome-mediated degradation (Yang et al. 2007).
Once MDM4 is phosphorylated by ATM and CHEK2 in response to DNA damage, MDM2 ubiquitinates MDM4 and targets it for degradation (Chen et al. 2005, Pereg et al. 2005). The presence of MDM4 stimulates auto-ubiquitination of MDM2 (Linares et al. 2003).
To efficiently function as an E3 ubiquitin ligase, MDM2 has to form dimers or higher order oligomers. MDM2 can homodimerize (Cheng et al. 2011) or heterodimerize with MDM4 (MDMX) (Sharp et al. 1999, Huang et al. 2011, Pant et al. 2011). Dimerization involves the RING domain of MDM2 and/or MDM4. Heterodimers of MDM2 and MDM4 may be particularly important during embryonic development (Pant et al. 2011).
TP53 (p53) functions as a stable homotetramer. The tetramerization domain is located within the C-terminus (Stenger et al. 1994, Waterman et al. 1995, Jeffrey et al. 1995, Wang et al. 1995).
MDM2 is an ubiquitin ligase whose expression is positively regulated by TP53 (p53) (Wu et al. 1993). MDM2 binds TP53 tetramer (Maki 1999) and promotes its ubiquitination and subsequent degradation (Fuchs et al. 1998). Formation of MDM2 homodimers (Cheng et al. 2011) or heterodimers with MDM4 (MDMX) is needed for efficient ubiquitination of TP53 (Linares et al. 2003). While MDM2-TP53 binding occurs at the amino-terminus of TP53, MDM2 ubiquitinates TP53 lysine residues at the carboxy-terminus. Acetylation of those lysines can inhibit MDM2-dependent ubiquitination (Li et al. 2002).
ATM phosphorylates MDM2 on three serine residues (S386, S395, S407) and one threonine residue (T419) in vicinity to the RING domain. ATM-mediated phosphorylation of MDM2 in response to DNA damage (DNA double strand breaks) prevents MDM2 dimerization, binding of TP53 (p53) and MDM2-mediated ubiquitination of TP53 (Cheng et al. 2009, Cheng et al. 2011).
Binding of p14-ARF to MDM2 decreases the half-life of MDM2, likely through promoting MDM2 degradation. Thus, p14-ARF inhibits MDM2-mediated ubiquitination and degradation of TP53 (Zhang et al. 1998).
p14-ARF forms a complex with TP53-bound MDM2 by interacting with the C-terminus of MDM2, while the N-terminus of MDM2 is involved in TP53 (p53) binding. p14-ARF cannot associate with TP53 in the absence of MDM2 (Zhang et al. 1998).
The ubiquitin protease USP2 forms a tripartite complex with MDM2 and MDM4 (MDMX) by binding to the ubiquitinated heterodimer of MDM2 and MDM4 (Allende-Vega et al. 2010).
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Activity through
PhosphorylationPhosphorylation of TP53 at serine residue S46 promotes transcription of TP53-regulated apoptotic genes rather than cell cycle arrest genes. Several kinases can phosphorylate S46 of TP53, including ATM-activated DYRK2, which, like TP53, is targeted for degradation by MDM2 (Taira et al. 2007, Taira et al. 2010). TP53 is also phosphorylated at S46 by HIPK2 in the presence of the TP53 transcriptional target TP53INP1 (D'Orazi et al. 2002, Hofmann et al. 2002, Tomasini et al. 2003). CDK5, in addition to phosphorylating TP53 at S15, also phosphorylates it at S33 and S46, which promotes neuronal cell death (Lee et al. 2007).
MAPKAPK5 (PRAK) phosphorylates TP53 at serine residue S37, promoting cell cycle arrest and cellular senescence in response to oncogenic RAS signaling (Sun et al. 2007).
NUAK1 phosphorylates TP53 at S15 and S392, and phosphorylation at S392 may contribute to TP53-mediated transcriptional activation of cell cycle arrest genes (Hou et al. 2011). S392 of TP53 is also phosphorylated by the complex of casein kinase II (CK2) bound to the FACT complex, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).
The activity of TP53 is inhibited by phosphorylation at serine residue S315, which enhances MDM2 binding and degradation of TP53. S315 of TP53 is phosphorylated by Aurora kinase A (AURKA) (Katayama et al. 2004) and CDK2 (Luciani et al. 2000). Interaction with MDM2 and the consequent TP53 degradation is also increased by phosphorylation of TP53 threonine residue T55 by the transcription initiation factor complex TFIID (Li et al. 2004).
Aurora kinase B (AURKB) has been shown to phosphorylate TP53 at serine residue S269 and threonine residue T284, which is possibly facilitated by the binding of the NIR co-repressor. AURKB-mediated phosphorylation was reported to inhibit TP53 transcriptional activity through an unknown mechanism (Wu et al. 2011). A putative direct interaction between TP53 and AURKB has also been described and linked to TP53 phosphorylation and S183, T211 and S215 and TP53 degradation (Gully et al. 2012).
dimer,
p-S166,S188-MDM2,MDM4:TP53dimer,
p-S166,S188-MDM2:MDM4Annotated Interactions
CCNG1-recruited PP2A can also dephosphorylate serine residue S166 of human MDM2 (Okamoto et al. 2002).
dimer,
p-S166,S188-MDM2,MDM4:TP53dimer,
p-S166,S188-MDM2,MDM4:TP53dimer,
p-S166,S188-MDM2,MDM4:TP53dimer,
p-S166,S188-MDM2,MDM4:TP53dimer,
p-S166,S188-MDM2:MDM4dimer,
p-S166,S188-MDM2:MDM4dimer,
p-S166,S188-MDM2:MDM4