Binding of TP53 (p53) to the p53 response element in the first intron of the BCL6 gene promotes BCL6 transcription (Margalit et al. 2006). BCL6 is a transcriptional repressor that has been implicated as a facilitator of apoptosis, through inhibition of BCL2 expression (Saito et al. 2009), but also as an inhibitor of apoptosis, through inhibition of TP53 expression (Phan and Dalla-Favera 2004).

TP53 (p53) binds the p53 response element located in the first intron of the BCL6 gene. This region of the BCL6 gene is frequently subject to translocations, point mutations and deletions in B-cell non-Hodgkin lymphoma (Margalit et al. 2006).

Transcription of the BCL6 gene, encoding a pro-apoptotic transcriptional repressor, is directly stimulated by FOXO3 (Fernandez de Mattos et al. 2004) and FOXO4 (AFX) (Tang et al. 2002). FOXO1 stimulates BCL6 gene transcription (Shore et al. 2006), but direct binding of FOXO1 to the BCL6 gene promoter has not been demonstrated.

FOXO3 (Fernandez de Mattos et al. 2004), FOXO4 (AFX) (Tang et al. 2002), and probably FOXO1 (Shore et al. 2006) bind to forkhead box elements in the promoter of the BCL6 gene.

Signal transducer and activator of transcription 3 (STAT3) is a key regulator of gene expression in response to signaling of many cytokines including interleukin-6 (IL6), Oncostatin M, and leukemia inhibitory factor. Using microarray techniques, hundreds of genes have been reported as potential STAT3 target genes (Dauer et al. 2005, Hsieh et al. 2005). Some of these genes have been proven to be direct STAT3 targets using genome-wide chromatin immunoprecipitation screening (Snyder et al. 2008, Carpenter & Lo 2014). Genes for nuclear proteins upregulated by STAT3 include CCAAT/enhancer-binding protein delta (CEBPD) (Hutt et al. 2000), B-cell lymphoma 6 protein (BCL6) (Reljic et al. 2000), Myc proto-oncogene protein (MYC) (Kiuchi et al. 1999, Bowman et al. 2001), Proto-oncogene c-Fos (FOS) (Yang et al. 2003), Hypoxia-inducible factor 1-alpha (HIF1A) (Niu et al. 2008), Transcription factor SOX-2 (SOX2) (Foshay & Gallicano 2008), the homeobox protein NANOG (Okumura et al. 2011), Twist-related protein 1 (TWIST1) (Lo et al. 2007, Cheng et al. 2008), Zinc finger E-box-binding homeobox 1 (ZEB1) (Xiong et al. 2012), POU domain, class 2, transcription factor 1 (POU2F1) (OCT1) (Wang et al. 2013), Baculoviral IAP repeat-containing protein 5 (BIRC5, Survivin) (Gritsko et al. 2006), G1/S-specific cyclin-D1 (CCND1) (Leslie et al. 2006), Serine/threonine-protein kinase PIM1 (Przanowski et al. 2014), Forkhead box protein O1 (FOXO1), FOXO3 (Oh et al. 2011), Nuclear receptor ROR-alpha (RORA), RORC, Basic leucine zipper transcriptional factor ATF-like (BATF) (Durant et al. 2010) and Transcription factor JUNB (Coffer et al. 1995).

The exact mechanisms of action of several other pro-apoptotic TP53 (p53) targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP, remain uncertain (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).

The tumor suppressor TP53 (p53) exerts its tumor suppressive role in part by regulating transcription of a number of genes involved in cell death, mainly apoptotic cell death. The majority of apoptotic genes that are transcriptional targets of TP53 promote apoptosis, but there are also several TP53 target genes that inhibit apoptosis, providing cells with an opportunity to attempt to repair the damage and/or recover from stress.
Pro-apoptotic transcriptional targets of TP53 involve TRAIL death receptors TNFRSF10A (DR4), TNFRSF10B (DR5), TNFRSF10C (DcR1) and TNFRSF10D (DcR2), as well as the FASL/CD95L death receptor FAS (CD95). TRAIL receptors and FAS induce pro-apoptotic signaling in response to external stimuli via extrinsic apoptosis pathway (Wu et al. 1997, Takimoto et al. 2000, Guan et al. 2001, Liu et al. 2004, Ruiz de Almodovar et al. 2004, Liu et al. 2005, Schilling et al. 2009, Wilson et al. 2013). IGFBP3 is a transcriptional target of TP53 that may serve as a ligand for a novel death receptor TMEM219 (Buckbinder et al. 1995, Ingermann et al. 2010).

TP53 regulates expression of a number of genes involved in the intrinsic apoptosis pathway, triggered by the cellular stress. Some of TP53 targets, such as BAX, BID, PMAIP1 (NOXA), BBC3 (PUMA) and probably BNIP3L, AIFM2, STEAP3, TRIAP1 and TP53AIP1, regulate the permeability of the mitochondrial membrane and/or cytochrome C release (Miyashita and Reed 1995, Oda et al. 2000, Samuels-Lev et al. 2001, Nakano and Vousden 2001, Sax et al. 2002, Passer et al. 2003, Bergamaschi et al. 2004, Li et al. 2004, Fei et al. 2004, Wu et al. 2004, Park and Nakamura 2005, Patel et al. 2008, Wang et al. 2012, Wilson et al. 2013). Other pro-apoptotic genes, either involved in the intrinsic apoptosis pathway, extrinsic apoptosis pathway or pyroptosis (inflammation-related cell death), which are transcriptionally regulated by TP53 are cytosolic caspase activators, such as APAF1, PIDD1, and NLRC4, and caspases themselves, such as CASP1, CASP6 and CASP10 (Lin et al. 2000, Robles et al. 2001, Gupta et al. 2001, MacLachlan and El-Deiry 2002, Rikhof et al. 2003, Sadasivam et al. 2005, Brough and Rothwell 2007).

It is uncertain how exactly some of the pro-apoptotic TP53 targets, such as TP53I3 (PIG3), RABGGTA, BCL2L14, BCL6, NDRG1 and PERP contribute to apoptosis (Attardi et al. 2000, Guo et al. 2001, Samuels-Lev et al. 2001, Contente et al. 2002, Ihrie et al. 2003, Bergamaschi et al. 2004, Stein et al. 2004, Phan and Dalla-Favera 2004, Jen and Cheung 2005, Margalit et al. 2006, Zhang et al. 2007, Saito et al. 2009, Davies et al. 2009, Giam et al. 2012).

TP53 is stabilized in response to cellular stress by phosphorylation on at least serine residues S15 and S20. Since TP53 stabilization precedes the activation of cell death genes, the TP53 tetramer phosphorylated at S15 and S20 is shown as a regulator of pro-apoptotic/pro-cell death genes. Some pro-apoptotic TP53 target genes, such as TP53AIP1, require additional phosphorylation of TP53 at serine residue S46 (Oda et al. 2000, Taira et al. 2007). Phosphorylation of TP53 at S46 is regulated by another TP53 pro-apoptotic target, TP53INP1 (Okamura et al. 2001, Tomasini et al. 2003). Additional post-translational modifications of TP53 may be involved in transcriptional regulation of genes presented in this pathway and this information will be included as evidence becomes available.

Activation of some pro-apoptotic TP53 targets, such as BAX, FAS, BBC3 (PUMA) and TP53I3 (PIG3) requires the presence of the complex of TP53 and an ASPP protein, either PPP1R13B (ASPP1) or TP53BP2 (ASPP2) (Samuels-Lev et al. 2001, Bergamaschi et al. 2004, Patel et al. 2008, Wilson et al. 2013), indicating how the interaction with specific co-factors modulates the cellular response/outcome.

TP53 family members TP63 and or TP73 can also activate some of the pro-apoptotic TP53 targets, such as FAS, BAX, BBC3 (PUMA), TP53I3 (PIG3), CASP1 and PERP (Bergamaschi et al. 2004, Jain et al. 2005, Ihrie et al. 2005, Patel et al. 2008, Schilling et al. 2009, Celardo et al. 2013).

For a review of the role of TP53 in apoptosis and pro-apoptotic transcriptional targets of TP53, please refer to Riley et al. 2008, Murray-Zmijewski et al. 2008, Bieging et al. 2014, Kruiswijk et al. 2015.

FOXO transcription factors promote expression of several pro-apoptotic genes, such as FASLG (Brunet et al. 1999, Ciechomska et al. 2003, Chen et al. 2013, Li et al. 2015), PINK1 (Mei et al. 2009, Sengupta et al. 2011), BCL2L11 (BIM) (Gilley et al. 2003, Urbich et al. 2005, Chuang et al. 2007, Hughes et al. 2011, Chen et al. 2013, Wang et al. 2016), BCL6 (Tang et al. 2002, Fernandez de Mattos et al. 2004, Shore et al. 2006) and BBC3 (PUMA) (Dudgeon et al. 2010, Hughes et al. 2011, Liu et al. 2015, Wu et al. 2016, Liu et al. 2017, Fitzwalter et al. 2018). FOXO-mediated induction of cell death genes is important during development, for example during nervous system development, where FOXO promotes neuronal death upon NGF withdrawal (Gilley et al. 2003), and also contributes to the tumor-suppressive role of FOXO factors (Arimoto Ishida et al. 2004). FOXO1 transcriptional activity is implicated in the cell death of enteric nervous system (ENS) precursors. RET signaling, which activates PI3K/AKT signaling, leading to inhibition of FOXO mediated transcription, ensures survival of ENS precursors (Srinivasan et al. 2005).
Transcription of the STK11 (LKB1) gene, encoding Serine/threonine-protein kinase STK11 (also known as Liver kinase B1), which regulates diverse cellular processes, including apoptosis, is directly stimulated by FOXO3 and FOXO4 (Lutzner et al. 2012).

Lysine deacetylases (KDACs), historically referred to as histone deacetylases (HDACs), are divided into the Rpd3/Hda1 metal-dependent 'classical HDAC family' (de Ruijter et al. 2003, Verdin et al. 2003) and the unrelated sirtuins (Milne & Denu 2008). Phylogenetic analysis divides human KDACs into four classes (Gregoretti et al. 2004): Class I includes HDAC1, 2, 3 and 8; Class IIa includes HDAC4, 5, 7 and 9; Class IIb includes HDAC6 and 10; Class III are the sirtuins (SIRT1-7); Class IV has one member, HDAC11 (Gao et al. 2002). Class III enzymes use an NAD+ cofactor to perform deacetylation (Milne & Denu 2008, Yang & Seto 2008), the others classes use a metal-dependent mechanism (Gregoretti et al. 2004) to catalyze the hydrolysis of acetyl-L-lysine side chains in histone and non-histone proteins yielding L-lysine and acetate. X-ray crystal structures are available for four human HDACs; these structures have conserved active site residues, suggesting a common catalytic mechanism (Lombardi et al. 2011). They require a single transition metal ion and are typically studied in vitro as Zn2+-containing enzymes, though in vivo HDAC8 exhibits increased activity when substituted with Fe2+ (Gantt et al. 2006). The structurally-related enzyme acetylpolyamine amidohydrolase (APAH) (Leipe & Landsman 1997) exhibits optimal activity with Mn2+, followed closely by Zn2+ (Sakurada et al. 1996).

HDACs are often part of multi-protein transcriptional complexes that are recruited to gene promoters, regulating transcription without direct DNA binding. With the exception of HDAC8, all class I members can be catalytic subunits of multiprotein complexes (Yang & Seto 2008). HDAC1 and HDAC2 interact to form the catalytic core of several multisubunit complexes including Sin3, nucleosome remodeling deacetylase (NuRD) and corepressor of REST (CoREST) complexes (Grozinger & Schreiber 2002). HDAC3 is part of the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) complex or the homologous nuclear receptor corepressor (NCoR) (Li et al. 2000, Wen et al. 2000, Zhang et al. 2002, Yoon et al. 2003, Oberoi et al. 2011) which are involved in a wide range of processes including metabolism, inflammation, and circadian rhythms (Mottis et al. 2013).

Class IIa HDACs (HDAC4, -5, -7, and -9) shuttle between the nucleus and cytoplasm (Yang & Seto 2008, Haberland et al. 2009). The nuclear export of class IIa HDACs requires phosphorylation stimulated by calcium or other stimuli. They appear to have been evolutionarily inactivated as enzymes, having acquired a histidine substitution of the tyrosine residue in the active site of the mammalian deacetylase domain (H976 in humans) (Lahm et al. 2007, Schuetz et al. 2008). Instead they function as transcriptional corepressors for the MEF2 family of transcription factors (Yang & Gregoire 2005) .

Histones are the primary substrate for most HDACs except HDAC6 which is predominantly cytoplasmic and acts on alpha-tublin (Hubbert et al. 2002, Zhang et al. 2003, Boyault et al. 2007). HDACs also deacetylate proteins such as p53, E2F1, RelA, YY1, TFIIE, BCL6 and TFIIF (Glozak et al. 2005).

Histone deacetylases are targeted by structurally diverse compounds known as HDAC inhibitors (HDIs) (Marks et al. 2000). These can induce cytodifferentiation, cell cycle arrest and apoptosis of transformed cells (Marks et al. 2000, Bolden et al. 2006). Some HDIs have significant antitumor activity (Marks and Breslow 2007, Ma et al. 2009) and at least two are approved anti-cancer drugs.

The coordinates of post-translational modifications represented and described here follow UniProt standard practice whereby coordinates refer to the translated protein before any further processing. Histone literature typically refers to coordinates of the protein after the initiating methionine has been removed. Therefore the coordinates of post-translated residues in the Reactome database and described here are frequently +1 when compared with the literature.