Thr18

Site Information
EPPLsQEtFsDLWkL SwissProt Entrez-Gene
Blast this site against: NCBI SwissProt PDB
Site Group ID: 447541

In vivo Characterization
Methods used to characterize site in vivo:	[32P] bio-synthetic labeling ( 26 ) , immunoprecipitation ( 15 , 22 ) , modification-specific antibody ( 16 , 20 ) , mutation of modification site ( 9 , 18 , 20 , 21 , 24 , 25 , 26 , 28 ) , phospho-antibody ( 1 , 3 , 4 , 6 , 9 , 11 , 14 , 15 , 16 , 18 , 20 , 22 , 27 , 28 ) , western blotting ( 1 , 3 , 4 , 6 , 9 , 11 , 14 , 15 , 16 , 20 , 27 , 28 )
Disease tissue studied:	ataxia-telangiectasia ( 22 ) , bone cancer ( 1 ) , colorectal cancer ( 9 , 14 , 20 ) , colorectal carcinoma ( 9 , 14 , 20 ) , leukemia ( 15 ) , acute myelogenous leukemia ( 15 ) , liver cancer ( 4 ) , hepatocellular carcinoma ( 4 ) , lung cancer ( 9 , 14 , 16 , 20 , 28 ) , non-small cell lung cancer ( 9 , 14 , 16 , 20 , 28 ) , non-small cell lung adenocarcinoma ( 9 , 16 ) , non-small cell squamous cell lung carcinoma ( 14 ) , neuroblastoma ( 22 )
Relevant cell line - cell type - tissue:	293 (epithelial) ( 6 ) , A375 (melanocyte) ( 25 ) , A549 (pulmonary) ( 9 , 14 , 16 , 18 , 20 , 28 ) , AT24RM (lymphoblastoid) ( 22 ) , BT (epithelial) ( 22 ) , C3ABR (lymphoblastoid) ( 22 ) , chondrocyte ( 21 ) , fibroblast ( 28 ) , GM01526 (lymphoblast) ( 22 ) , GM02254 (lymphoblast) ( 22 ) , HCA2 (fibroblast) [TERT (human), transfection] ( 27 ) , HCT116 (intestinal) ( 9 , 14 , 20 ) , Huh7 (hepatic) ( 4 ) , IMR-90 (fibroblast) ( 3 ) , L3 (lymphoblastoid) ( 22 ) , MDAH041 (fibroblast) ( 24 ) , MEF (fibroblast) [PML (human)] ( 15 ) , MEF (fibroblast) ( 20 ) , MRC5 (fibroblast) ( 20 ) , NB-4 (myeloid) ( 15 ) , NCI-H1299 (pulmonary) ( 9 , 14 , 16 , 18 , 20 , 26 , 28 ) , NCI-H1650 (pulmonary) ( 14 ) , NCI-H1703 (squamous) ( 14 ) , NCI-H23 (pulmonary) ( 14 ) , NCI-H460 (pulmonary) ( 14 ) , Saos-2 (bone cell) ( 25 ) , SHEP (neuron) ( 22 ) , U2OS (bone cell) ( 1 ) , WS1 (fibroblast) ( 11 , 20 , 28 )

Upstream Regulation
Regulatory protein:	IFI16 (human) ( 1 ) , LKB1 (human) ( 14 ) , PCNA (human) ( 6 ) , plakophilin 2 (human) ( 4 ) , TERT (human) ( 27 ) , VRK1 (human) ( 4 , 11 )
Putative in vivo kinases:	CK1A (human) ( 15 ) , VRK1 (human) ( 4 , 18 )
Kinases, in vitro:	AMPKA1 (human) ( 17 ) , Chk1 (human) ( 17 ) , Chk2 (human) ( 17 , 29 ) , CK1D (human) ( 28 , 30 ) , DAPK1 (human) ( 17 ) , DNAPK (human) ( 19 ) , VRK1 (human) ( 18 )
Putative upstream phosphatases:	CDC25B (human) ( 3 )
Treatments:	5-aza-CdR ( 16 ) , adriamycin ( 18 , 22 ) , As2O3 ( 15 ) , bleomycin ( 27 ) , depsipeptide ( 9 ) , development ( 27 ) , high_glucose ( 4 ) , IC261 ( 15 ) , ionizing_radiation ( 15 , 20 , 22 , 27 , 28 ) , leptomycin_B ( 11 ) , low_glucose ( 4 ) , NaB ( 9 ) , nocodazole ( 20 ) , nutlin-3 ( 1 ) , PALA ( 20 ) , serum_starvation ( 27 ) , siRNA ( 4 , 14 ) , taxol ( 20 , 26 ) , trichostatin_A ( 9 ) , UV ( 11 , 20 , 27 )

Downstream Regulation
Effects of modification on p53:	acetylation ( 9 , 20 , 22 ) , molecular association, regulation ( 2 , 5 , 7 , 8 , 9 , 12 , 13 , 25 , 28 ) , protein conformation ( 5 , 7 , 8 ) , protein degradation ( 3 ) , protein stabilization ( 12 , 18 )
Effects of modification on biological processes:	apoptosis, altered ( 14 ) , carcinogenesis, induced ( 3 ) , cell cycle regulation ( 3 ) , cell growth, induced ( 3 ) , transcription, altered ( 25 ) , transcription, induced ( 9 )
Induce interaction with:	CBP (human) ( 7 , 12 ) , DNA ( 9 ) , S100A1 (human) ( 13 ) , S100A2 (human) ( 13 ) , S100A4 (human) ( 13 ) , S100A6 (human) ( 13 ) , S100B (human) ( 13 ) , p300 (human) ( 25 )
Inhibit interaction with:	MDM2 (human) ( 2 , 5 , 8 , 28 )

References
1	Li D, et al. (2021) STING-mediated degradation of IFI16 negatively regulates apoptosis by inhibiting p53 phosphorylation at serine 392. J Biol Chem 297, 100930 34216619 Curated Info
2	Oh S, Lee MK, Chi SW (2021) Single-molecule analysis of interaction between p53TAD and MDM2 using aerolysin nanopores. Chem Sci 12, 5883-5891 34168813 Curated Info
3	Chen YC, et al. (2021) CDC25B induces cellular senescence and correlates with tumor suppression in a p53-dependent manner. J Biol Chem 296, 100564 33745968 Curated Info
4	Yokobori K, Miyauchi Y, Williams JG, Negishi M (2020) Phosphorylation of vaccinia-related kinase 1 at threonine 386 transduces glucose stress signal in human liver cells. Biosci Rep 40 32266931 Curated Info
5	Yadahalli S, et al. (2019) Kinetic and thermodynamic effects of phosphorylation on p53 binding to MDM2. Sci Rep 9, 693 30679555 Curated Info
6	Qin Z, et al. (2016) PCNA-Ub polyubiquitination inhibits cell proliferation and induces cell-cycle checkpoints. Cell Cycle 15, 3390-3401 27753536 Curated Info
7	Ithuralde RE, Turjanski AG (2016) Phosphorylation Regulates the Bound Structure of an Intrinsically Disordered Protein: The p53-TAZ2 Case. PLoS One 11, e0144284 26742101 Curated Info
8	ElSawy KM, et al. (2015) A spatiotemporal characterization of the effect of p53 phosphorylation on its interaction with MDM2. Cell Cycle 14, 179-88 25584963 Curated Info
9	Wang H, et al. (2012) The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair (Amst) 11, 146-56 22112863 Curated Info
10	Verkhivker GM (2012) Simulating Molecular Mechanisms of the MDM2-Mediated Regulatory Interactions: A Conformational Selection Model of the MDM2 Lid Dynamics. PLoS One 7, e40897 22815859 Curated Info
11	Valbuena A, Castro-Obregón S, Lazo PA (2011) Downregulation of VRK1 by p53 in response to DNA damage is mediated by the autophagic pathway. PLoS One 6, e17320 21386980 Curated Info
12	Lee CW, et al. (2010) Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation. Proc Natl Acad Sci U S A 107, 19290-5 20962272 Curated Info
13	van Dieck J, et al. (2009) Posttranslational modifications affect the interaction of S100 proteins with tumor suppressor p53. J Mol Biol 394, 922-30 19819244 Curated Info
14	Zhong D, et al. (2008) LKB1 is necessary for Akt-mediated phosphorylation of proapoptotic proteins. Cancer Res 68, 7270-7 18794113 Curated Info
15	Alsheich-Bartok O, et al. (2008) PML enhances the regulation of p53 by CK1 in response to DNA damage. Oncogene 27, 3653-61 18246126 Curated Info
16	Wang H, et al. (2008) An ATM- and Rad3-related (ATR) Signaling Pathway and a Phosphorylation-Acetylation Cascade Are Involved in Activation of p53/p21Waf1/Cip1 in Response to 5-Aza-2'-deoxycytidine Treatment. J Biol Chem 283, 2564-74 17977830 Curated Info
17	Craig AL, et al. (2007) The MDM2 ubiquitination signal in the DNA-binding domain of p53 forms a docking site for calcium calmodulin kinase superfamily members. Mol Cell Biol 27, 3542-55 17339337 Curated Info
18	Vega FM, Sevilla A, Lazo PA (2004) p53 Stabilization and accumulation induced by human vaccinia-related kinase 1. Mol Cell Biol 24, 10366-80 15542844 Curated Info
19	Soubeyrand S, Schild-Poulter C, Haché RJ (2004) Structured DNA promotes phosphorylation of p53 by DNA-dependent protein kinase at serine 9 and threonine 18. Eur J Biochem 271, 3776-84 15355354 Curated Info
20	Saito S, et al. (2003) Phosphorylation site interdependence of human p53 post-translational modifications in response to stress. J Biol Chem 278, 37536-44 12860987 Curated Info
21	Kim SJ, et al. (2002) p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation. J Biol Chem 277, 33501-8 12091386 Curated Info
22	Saito S, et al. (2002) ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. J Biol Chem 277, 12491-4 11875057 Curated Info
23	Barcia R, López-Borges S, Vega FM, Lazo PA (2002) Kinetic properties of p53 phosphorylation by the human vaccinia-related kinase 1. Arch Biochem Biophys 399, 1-5 11883897 Curated Info
24	Bean LJ, Stark GR (2002) Regulation of the accumulation and function of p53 by phosphorylation of two residues within the domain that binds to Mdm2. J Biol Chem 277, 1864-71 11707453 Curated Info
25	Dornan D, Hupp TR (2001) Inhibition of p53-dependent transcription by BOX-I phospho-peptide mimetics that bind to p300. EMBO Rep 2, 139-44 11258706 Curated Info
26	Stewart ZA, Tang LJ, Pietenpol JA (2001) Increased p53 phosphorylation after microtubule disruption is mediated in a microtubule inhibitor- and cell-specific manner. Oncogene 20, 113-24 11244509 Curated Info
27	Webley K, et al. (2000) Posttranslational modifications of p53 in replicative senescence overlapping but distinct from those induced by DNA damage. Mol Cell Biol 20, 2803-8 10733583 Curated Info
28	Sakaguchi K, et al. (2000) Damage-mediated phosphorylation of human p53 threonine 18 through a cascade mediated by a casein 1-like kinase. Effect on Mdm2 binding. J Biol Chem 275, 9278-83 10734067 Curated Info
29	Shieh SY, et al. (2000) The human homologs of checkpoint kinases Chk1 and Cds1 (Chk2) phosphorylate p53 at multiple DNA damage-inducible sites. Genes Dev 14, 289-300 10673501 Curated Info
30	Dumaz N, Milne DM, Meek DW (1999) Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phosphorylation of serine 15. FEBS Lett 463, 312-6 10606744 Curated Info