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).<p>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).<p>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).<p>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).<p>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).
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Oxidative stress, caused by increased concentration of reactive oxygen species (ROS) in the cell, can happen as a consequence of mitochondrial dysfunction induced by the oncogenic RAS (Moiseeva et al. 2009) or independent of oncogenic signaling. Prolonged exposure to interferon-beta (IFNB, IFN-beta) also results in ROS increase (Moiseeva et al. 2006). ROS oxidize thioredoxin (TXN), which causes TXN to dissociate from the N-terminus of MAP3K5 (ASK1), enabling MAP3K5 to become catalytically active (Saitoh et al. 1998). ROS also stimulate expression of Ste20 family kinases MINK1 (MINK) and TNIK through an unknown mechanism, and MINK1 and TNIK positively regulate MAP3K5 activation (Nicke et al. 2005).
MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
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).
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).
DSIF is a heterodimer consisting of hSPT4 (human homolog of yeast Spt4- p14) and hSPT5 (human homolog of yeast Spt5-p160). DSIF association with Pol II may be enabled by Spt5 binding to Pol II creating a scaffold for NELF binding (Wada et al.,1998). Spt5 subunit of DSIF can be phosphorylated by P-TEFb.
TP53INP1 (p53INP1) forms a complex with TP53 and its regulating kinase HIPK2 (Tomasini et al. 2003, Okamura et al. 2001). HIPK2 undergoes autophosphorylation in response to DNA damage, but the mechanism and the identity of autophosphorylation sites have not yet been fully elucidated (Bitomsky et al. 2013, Saul et al. 2013, Siepi et al. 2013). Autophosphorylation enables HIPK2 binding to PIN1. PIN1 likely facilitates a conformational change that enables HIPK2 to phosphorylate its targets, including TP53 (Bitomsky et al. 2013).
NUAK1, activated by STK11 (LKB1)-mediated phosphorylation on threonine residue T211, phosphorylates TP53 (p53) on serine residues S15 and S392, contributing to TP53-mediated transcriptional activation of the CDKN1A (p21) gene (Zeng and Berger 2006, Hou et al. 2011).
NOC2L (NIR) is an inhibitor of histone acetyltransferases that associates with TP53 (p53). NOC2L binding represses TP53-mediated transcriptional activation at TP53 target genes. One possible mechanism is the prevention of activating histone acetylation at TP53 target genes (Hublitz et al. 2005).
Activated MAPKAPK5 (PRAK) phosphorylates TP53 (p53) on serine residue S37, thereby activating it. MAPKAPK5-mediated phosphorylation of TP53 promotes growth arrest and senescence induced by oncogenic RAS, but is not needed for TP53-dependent growth arrest in response to DNA damage (Sun et al. 2007).
In response to DNA double strand breaks, serine at position 15 of the TP53 (p53) tumor suppressor protein is rapidly phosphorylated by the ATM kinase. This serves to stabilize the p53 protein. A rise in the levels of the p53 protein induces the expression of p21 cyclin-dependent kinase inhibitor. This prevents the normal progression from G1 to S phase, thus providing a check on replication of damaged DNA (Banin et al. 1998, Canman et al. 1998, Khanna et al. 1998).
Activated ATM kinase phosphorylates DYRK2 at threonine residue T106 (matching T33 in the shorter splicing isoform of DYRK2) and serine residue S442 (matching S369 in the shorter splicing isoform of DYRK2). ATM-mediated phosphorylation of DYRK2 prevents DYRK2 ubiquitination by MDM2 and the consequent DYRK2 degradation (Taira et al. 2010).
MDM2 ubiquitinates DYRK2 in the nucleus, leading to proteasome-mediated degradation of DYRK2. This results in the removal of nuclear DYRK2 and exclusive localization of DYRK2 in the cytosol in the absence of DNA damage. ATM-mediated phosphorylation of DYRK2 prevents ubiquitination of DYRK2 by MDM2, leading to accumulation of nuclear DYRK2 (Taira et al. 2010).
CHEK1, activated by ATR-mediated phosphorylation, can phosphorylate TP53 at serine residue S20, resulting in the increased half-life of TP53 (Shieh et al. 2000).
ATR, bound to DNA damage sites, phosphorylates TP53 (p53) at serine residue S15. S15 phosphorylation stabilizes TP53 by inhibiting the binding of TP53 to the ubiquitin ligase MDM2 (Tibbetts et al. 1999, Lakin et al. 1999).
HIPK2, activated by autophosphorylation in response to DNA damage, phosphorylates TP53 (p53) at serine residue S46 (D'Orazi et al. 2002, Hofmann et al. 2002). A TP53 transcriptional target TP53INP1 facilitates TP53 phosphorylation at S46 in response to double strand breaks and, together with HIPK2, promotes the transcription of TP53 apoptotic gene targets (Okamura et al. 2001, Tomasini et al. 2003).
TP53 (p53) forms a complex with a protein kinase HIPK1 (Kondo et al. 2003, Rey et al. 2013). HIPK1 may phosphorylate TP53 on an unidentified serine residue (Kondo et al. 2003). Binding to HIPK1 has been implicated in the negative regulation of TP53 activity (Kondo et al. 2003), but HIPK1 overexpression has also been implicated in the positive regulation of TP53 activity (Rey et al. 2013).
Casein kinase II (CK2), associated with the FACT2 complex, phosphorylates TP53 (p53) at serine residue S392, enhancing transcriptional activity of TP53 in response to UV irradiation (Keller et al. 2001, Keller and Lu 2002).
AURKA (Aurora kinase A) phosphorylates TP53 (p53) on serine residue S315. This leads to destabilization of TP53 by enhancing MDM2 binding (Katayama et al. 2004). Based on Xenopus studies, AURKA-mediated phosphorylation of TP53 occurs in the presence of AURKA activator TPX2 (Pascreau et al. 2009).
AURKB (Aurora kinase B) phosphorylates TP53 (p53) at serine residue S269 and threonine residue T284, which inhibits TP53 transcriptional activity (Wu et al. 2011).
CDK5, in complex with cleaved CDK5R1 (p25), which ensures nuclear localization (Patrick et al. 1999, Lee et al. 2008), phosphorylates TP53 (p53) on serine residues S15, S33 and S46. CDK5-mediated phosphorylation of TP53 promotes transcription of pro-apoptotic genes and neuronal cell death (Zhang et al. 2002, Lee et al. 2007, Lee et al. 2008).
TAF1, the largest subunit of the transcription initiation factor TFIID complex, phosphorylates TP53 (p53) at threonine residue T55. TAF1-mediated phosphorylation of TP53 increases affinity of TP53 for the ubiquitin ligase MDM2, thus promoting TP53 degradation (Li et al. 2004).
AMPK, activated in response to glucose deprivation, phosphorylates TP53 (p53) on serine residue S15, initiating AMPK-dependent cell cycle arrest (Jones et al. 2005). AMPK-dependent phosphorylation of TP73 (p73) appears to be involved in TP53 stabilization upon AMPK activation (Adamovich et al. 2014).
The atypical protein serine/threonine kinase TP53RK (TP53-regulating kinase), also known as PRPK (p53-related protein kinase), phosphorylates TP53 (p53) on serine residue S15 (Abe et al. 2001, Facchin et al. 2003).
CHEK2 (Chk2) phosphorylates TP53 (p53) at serine residue S20 (Hirao et al. 2000, Shieh et al. 2000, Chehab et al. 2000). Phosphorylation of TP53 at serine residue S20 is necessary for DNA damage-induced TP53 stabilization as it compromises the interaction of TP53 with the ubiquitin ligase MDM2 (Chehab et al. 1999, Chehab et al. 2000). S20 phosphorylation is also required for the induction of TP53-dependent transcripts in response to DNA damage (Hirao et al. 2000).
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overhanging
ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1MAP3K5 phosphorylates and activates MAP2K3 (MKK3) and MAP2K6 (MKK6) (Ichijo et al. 1997, Takekawa et al. 2005), which act as p38 MAPK kinases, as well as MAP2K4 (SEK1) (Ichijo et al. 1997, Matsuura et al. 2002), which, together with MAP2K7 (MKK7), acts as a JNK kinase.
MKK3 and MKK6 phosphorylate and activate p38 MAPK alpha (MAPK14) and beta (MAPK11) (Raingeaud et al. 1996), enabling p38 MAPKs to phosphorylate and activate MAPKAPK2 (MK2) and MAPKAPK3 (MK3) (Ben-Levy et al. 1995, Clifton et al. 1996, McLaughlin et al. 1996, Sithanandam et al. 1996, Meng et al. 2002, Lukas et al. 2004, White et al. 2007), as well as MAPKAPK5 (PRAK) (New et al. 1998 and 2003, Sun et al. 2007).
Phosphorylation of JNKs (MAPK8, MAPK9 and MAPK10) by MAP3K5-activated MAP2K4 (Deacon and Blank 1997, Fleming et al. 2000) allows JNKs to migrate to the nucleus (Mizukami et al. 1997) where they phosphorylate JUN. Phosphorylated JUN binds FOS phosphorylated by ERK1 or ERK2, downstream of activated RAS (Okazaki and Sagata 1995, Murphy et al. 2002), forming the activated protein 1 (AP-1) complex (FOS:JUN heterodimer) (Glover and Harrison 1995, Ainbinder et al. 1997).
Activation of p38 MAPKs and JNKs downstream of MAP3K5 (ASK1) ultimately converges on transcriptional regulation of CDKN2A locus. In dividing cells, nucleosomes bound to the CDKN2A locus are trimethylated on lysine residue 28 of histone H3 (HIST1H3A) by the Polycomb repressor complex 2 (PRC2), creating the H3K27Me3 (Me3K-28-HIST1H3A) mark (Bracken et al. 2007, Kotake et al. 2007). The expression of Polycomb constituents of PRC2 (Kuzmichev et al. 2002) - EZH2, EED and SUZ12 - and thereby formation of the PRC2, is positively regulated in growing cells by E2F1, E2F2 and E2F3 (Weinmann et al. 2001, Bracken et al. 2003). H3K27Me3 mark serves as a docking site for the Polycomb repressor complex 1 (PRC1) that contains BMI1 (PCGF4) and is therefore named PRC1.4, leading to the repression of transcription of p16INK4A and p14ARF from the CDKN2A locus, where PCR1.4 mediated repression of p14ARF transcription in humans may be context dependent (Voncken et al. 2005, Dietrich et al. 2007, Agherbi et al. 2009, Gao et al. 2012). MAPKAPK2 and MAPKAPK3, activated downstream of the MAP3K5-p38 MAPK cascade, phosphorylate BMI1 of the PRC1.4 complex, leading to dissociation of PRC1.4 complex from the CDKN2A locus and upregulation of p14ARF transcription (Voncken et al. 2005). AP-1 transcription factor, formed as a result of MAP3K5-JNK signaling, as well as RAS signaling, binds the promoter of KDM6B (JMJD3) gene and stimulates KDM6B expression. KDM6B is a histone demethylase that removes H3K27Me3 mark i.e. demethylates lysine K28 of HIST1H3A, thereby preventing PRC1.4 binding to the CDKN2A locus and allowing transcription of p16INK4A (Agger et al. 2009, Barradas et al. 2009, Lin et al. 2012).
p16INK4A inhibits phosphorylation-mediated inactivation of RB family members by CDK4 and CDK6, leading to cell cycle arrest (Serrano et al. 1993). p14ARF inhibits MDM2-mediated degradation of TP53 (p53) (Zhang et al. 1998), which also contributes to cell cycle arrest in cells undergoing oxidative stress. In addition, phosphorylation of TP53 by MAPKAPK5 (PRAK) activated downstream of MAP3K5-p38 MAPK signaling, activates TP53 and contributes to cellular senescence (Sun et al. 2007).
Expression and
DegradationActivating 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).
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).
dimer,
p-S166,S188-MDM2:MDM4Annotated Interactions
overhanging
ssDNA-DSBs:p-MRN:p-S1981,Ac-K3016-ATM:KAT5:BRCA1-C complex:EXO1,DNA2:BLM,WRN:p-S990,Ac-K1249-BRIP1:RAD17:RFC:RAD9:HUS1:RAD1:RHNO1:TOPBP1dimer,
p-S166,S188-MDM2:MDM4