id: PW:0000718 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0000718 title: p53 signaling pathway description: The p53 tumor suppression transcription factor, many times referred to as the 'guardian of the genome' or as the 'cellular gatekeeper', is at the hub of many signaling and regulatory networks. It represents a critical node of cellular homeostasis integrating many cues emerging from exogenous and endogenous stresses and in response promoting, as necessary, cell cycle arrest, apoptosis or senescence, among others. A key signal activating the p53 pathway is DNA damage, such as double-strand breaks(DSBs). The cells possess a robust response mechanism to DNA lesions, which triggers a range of signals to adequately handle the damage and maintain genomic integrity, collectively known as the DNA damage response (DDR). Central to mediating the response are the DDR kinases - ataxia telangiectasia-mutated (ATM), ATM and RAD3-related (ATR) and DNA-dependent protein kinase (DNA-PKcs). Of these, ATM plays a pivotal role - its signaling is activated by DSBs to promote the double-strand repair and prompt cell cycle checkpoint pathways, regulate cell fate decision (apoptosis or senescence), transcription and metabolic pathways. Of these, some are mediated by activation of p53 signaling. Distinct types of stress and/or damage summon distinct detection and/or repair proteins which in turn, via post-translational modifications and protein-protein interactions, relay the message to p53. The result is increased stabilization and reduced repression of p53, enhanced sequence specific DNA binding and regulation of transcription of many target genes. It is believed that hundreds of RNA polymerase II-transcribed genes are directly regulated by p53 and possibly thousands, indirectly. p53 consists of several domains - the N-terminal transactivation domain (TAD) with the two subdomains TAD-I (residues 20-40 - click to see the structure of a TAD-I fragment in complex with MDM2 from Xenopus Laevis ) and Tad-II (residues 40-60, a proline rich domain (residues 63-97) the evolutionary conserved DNA-binding domain (DBD - click to see the DBD in complex with DNA ) (residues 100-300), a linker region ( residues 301-323) a tetramerization domain (tet - click to see the tet domain ) (residues 324-355) and the basic carboxy-terminus domain (CTD) (residues 360-393). In the unstressed state, Mdm2 binds to and sterically blocks the transactivation domain of p53, it also acts as an E3 ubiquitin ligase for p53 and itself. Mdm2 is a target of p53, hence the negative feedback loop it provides. The structurally related Mdm4 (Mdmx) also negatively regulates p53. Stresses disrupt the p53-Mdm2 interaction, stabilize p53 or destabilize Mdm2. Once stabilized, p53 translocates to the nucleus where it binds to its response elements (RE) as a tetramer (dimer of dimers). Binding to DNA is dependent on the ability of DBD to co-ordinate a Zn++ ion through several cysteine residues. DNA binding also results in structural changes as evidenced in bending of DNA. Once bound, p53 recruits histone modifying enzymes, of which the acetyltransferases are best documented. The subsequent loosening of chromatin structure allows for the assembly of transcriptional machinery and initiation of RNA polymerase II transcription of target genes (p53 may also play a role in the elongation phase of RNA polII transcription). In contrast, p53 may inhibit transcription from RNA polymerase I and III (not shown). p53 is the target of numerous modifications that modulate its activity (see p53 regulators) and for many interacting partners via its domains (see p53 interacting partners). Target genes are regulated in a context-, locus- and stimulus-specific manner, with Tp53 being both an activator and also a repressor (see p53 targets). Tp53 can repress gene expression directly or indirectly via sequestration of other transcription factors or via non-coding RNA targets (see p53 targets). Many microRNAs (miRNAs) have been reported as targets of which some provide p53 regulatory feedback or further its function. In addition, evidence is emerging for the role of long non-coding RNA (lncRNAs) as both regulators and effectors of p53 (see non-coding RNA, p53 targets, regulators, effectors). It is well known that p53 is mutated in many types of cancer with over 50% of tumors exhibiting variation at this locus. Many mutations 'cluster' within the DBD domain and many result in a pro-oncogenic protein. In addition, tumors also exhibit amplification of both Mdm2 and Mdm4 genes; the two genes are reported to also have p53 independent functions. diagram_image: https://rgd.mcw.edu/pathway/PW0000718/p53%20signaling%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0000718/p53%20signaling%20pathway/p53%20signaling%20pathway.gpp diagram_pathway_links: - id: PW:0000104 label: intrinsic apoptotic pathway - id: PW:0000127 label: RNA polymerase II transcription pathway - id: PW:0001274 label: RNA polymerase II transcription initiation pathway - id: PW:0001361 label: ataxia telangiectasia-mutated (ATM) signaling pathway diagram_gene_links: - id: RGD:1305332 label: Mdm2 - id: RGD:1309306 label: Mdm4 - id: RGD:3889 label: Tp53 diagram_chemicals: - id: CHEBI:16480 label: 'NO' diagram_edges: - source: Mdm2 relation: associated_with target: Mdm4 - source: Mdm2 relation: associated_with target: Tp53 - source: Mdm2 relation: negatively_affects target: Tp53 - source: Mdm4 relation: associated_with target: Tp53 - source: Mdm4 relation: negatively_affects target: Tp53 - source: Tp53 relation: mutually_affects target: non-coding RNAs - p53 targets, regulators, effectors - source: Tp53 relation: positively_affects target: Mdm2 - source: Tp53 relation: positively_affects target: non-coding RNAs - p53 targets, regulators, effectors - source: Tp53 relation: positively_affects target: p53 targets - source: ataxia telangiectasia-mutated (ATM) signaling pathway relation: positively_affects target: p53, Mdm2 phosphorylation - source: p53 binding partners relation: associated_with target: Tp53 - source: p53 methylation relation: positively_affects target: Tp53 - source: p53, Mdm2 acetylation relation: negatively_affects target: Mdm2 - source: p53, Mdm2 acetylation relation: positively_affects target: Tp53 - source: p53, Mdm2 phosphorylation relation: positively_affects target: Mdm2 - source: p53, Mdm2 phosphorylation relation: positively_affects target: Tp53 - source: p53-dependent histone acetylation relation: associated_with target: Tp53 diagram_labels: - ataxia telangiectasia-mutated (ATM) signaling pathway --+> Tp53 - cell cycle arrest - endogenous stress - endogenous stress --+> Tp53 - exogenous stress - exogenous stress --+> Tp53 - p53 methylation - p53 ubiquitination - p53, Mdm2 acetylation - p53, Mdm2 phosphorylation - senescence - Tp53 --+> cell cycle arrest - Tp53 --+> intrinsic apoptotic pathway - Tp53 --+> RNA polymerase II transcription pathway - Tp53 --+> senescence diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/non-coding-rnas-p53-targets-regulators-effectors label: non-coding RNAs - p53 targets, regulators, effectors - href: /wg/home/pathway2/molecular-pathways2/p53-dependent-histone-acetylation label: p53-dependent histone acetylation - href: /wg/home/pathway2/molecular-pathways2/p53-regulators label: p53 regulators - href: /wg/home/pathway2/molecular-pathways2/p53-targets label: p53 targets - href: /wg/home/pathway2/molecular-pathways2/tp53-binding-partners label: p53 binding partners references: - id: RGD:2316155 citation: 'Kruse JP and Gu W, Cell. 2009 May 15;137(4):609-22. doi: 10.1016/j.cell.2009.04.050.' - id: RGD:2316156 citation: Lavin MF and Gueven N, Cell Death Differ. 2006 Jun;13(6):941-50. - id: RGD:2316186 citation: Whibley C, etal., Nat Rev Cancer. 2009 Feb;9(2):95-107. - id: RGD:5129813 citation: Harris SL and Levine AJ, Oncogene. 2005 Apr 18;24(17):2899-908. - id: RGD:5129843 citation: Brooks CL and Gu W, Mol Cell. 2006 Feb 3;21(3):307-15. - id: RGD:5129856 citation: Laptenko O and Prives C, Cell Death Differ. 2006 Jun;13(6):951-61. - id: RGD:5129869 citation: Kitayner M, etal., Mol Cell. 2006 Jun 23;22(6):741-53. - id: RGD:5129933 citation: Tidow H, etal., Proc Natl Acad Sci U S A. 2007 Jul 24;104(30):12324-9. 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