Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT1QOKLD)

• DOT Name: Protein AATF (AATF)
• Synonyms: Apoptosis-antagonizing transcription factor; Rb-binding protein Che-1
• Gene Name: AATF
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Amyotrophic lateral sclerosis
  Arthritis
  Bone osteosarcoma
  Carcinoma
  Colon carcinoma
  Creutzfeldt Jacob disease
  Endometrial carcinoma
  Hepatocellular carcinoma
  Lung cancer
  Lung carcinoma
  Myocardial infarction
  Neoplasm
  Nephronophthisis
  Neuroblastoma
  Non-alcoholic fatty liver disease
  Osteosarcoma
  Pharyngeal squamous cell carcinoma
  Plasma cell myeloma
  Hereditary breast carcinoma
  Small lymphocytic lymphoma
  Tetralogy of fallot
  Breast cancer
  Breast carcinoma
  Childhood kidney Wilms tumor
  Keratoconjunctivitis sicca
  Wilms tumor
• UniProt ID: AATF_HUMAN
• PDB ID: 5W6A; 7MQ8; 7MQ9
• Pfam ID: PF13339 ; PF08164
• Sequence:
  MAGPQPLALQLEQLLNPRPSEADPEADPEEATAARVIDRFDEGEDGEGDFLVVGSIRKLA
  SASLLDTDKRYCGKTTSRKAWNEDHWEQTLPGSSDEEISDEEGSGDEDSEGLGLEEYDED
  DLGAAEEQECGDHRESKKSRSHSAKTPGFSVQSISDFEKFTKGMDDLGSSEEEEDEESGM
  EEGDDAEDSQGESEEDRAGDRNSEDDGVVMTFSSVKVSEEVEKGRAVKNQIALWDQLLEG
  RIKLQKALLTTNQLPQPDVFPLFKDKGGPEFSSALKNSHKALKALLRSLVGLQEELLFQY
  PDTRYLVDGTKPNAGSEEISSEDDELVEEKKQQRRRVPAKRKLEMEDYPSFMAKRFADFT
  VYRNRTLQKWHDKTKLASGKLGKGFGAFERSILTQIDHILMDKERLLRRTQTKRSVYRVL
  GKPEPAAQPVPESLPGEPEILPQAPANAHLKDLDEEIFDDDDFYHQLLRELIERKTSSLD
  PNDQVAMGRQWLAIQKLRSKIHKKVDRKASKGRKLRFHVLSKLLSFMAPIDHTTMNDDAR
  TELYRSLFGQLHPPDEGHGD
• Function: Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome. May function as a general inhibitor of the histone deacetylase HDAC1. Binding to the pocket region of RB1 may displace HDAC1 from RB1/E2F complexes, leading to activation of E2F target genes and cell cycle progression. Conversely, displacement of HDAC1 from SP1 bound to the CDKN1A promoter leads to increased expression of this CDK inhibitor and blocks cell cycle progression. Also antagonizes PAWR mediated induction of aberrant amyloid peptide production in Alzheimer disease (presenile and senile dementia), although the molecular basis for this phenomenon has not been described to date.
• Tissue Specificity: Ubiquitously expressed. Expressed at high levels in brain, heart, kidney, placenta and thymus.
• Reactome Pathway: NRAGE signals death through JNK (R-HSA-193648)

Molecular Interaction Atlas (MIA) of This DOT

28 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Biomarker	[2]
Amyotrophic lateral sclerosis	DISF7HVM	Strong	Biomarker	[3]
Arthritis	DIST1YEL	Strong	Genetic Variation	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Carcinoma	DISH9F1N	Strong	Altered Expression	[6]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[6]
Creutzfeldt Jacob disease	DISCB6RX	Strong	Biomarker	[3]
Endometrial carcinoma	DISXR5CY	Strong	Biomarker	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[8]
Lung cancer	DISCM4YA	Strong	Biomarker	[1]
Lung carcinoma	DISTR26C	Strong	Biomarker	[1]
Myocardial infarction	DIS655KI	Strong	Biomarker	[9]
Neoplasm	DISZKGEW	Strong	Altered Expression	[10]
Nephronophthisis	DISXU4HY	Strong	Altered Expression	[11]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[12]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Biomarker	[8]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Pharyngeal squamous cell carcinoma	DISWZMVP	Strong	Biomarker	[13]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[5]
Hereditary breast carcinoma	DISAEZT5	moderate	Genetic Variation	[14]
Small lymphocytic lymphoma	DIS30POX	moderate	Altered Expression	[15]
Tetralogy of fallot	DISMHFNW	moderate	Biomarker	[16]
Breast cancer	DIS7DPX1	Limited	Biomarker	[5]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[5]
Childhood kidney Wilms tumor	DIS0NMK3	Limited	Altered Expression	[10]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[17]
Wilms tumor	DISB6T16	Limited	Altered Expression	[10]

6 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein AATF (AATF).	[18]
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the ADP-ribosylation of Protein AATF (AATF).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the phosphorylation of Protein AATF (AATF).	[23]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein AATF (AATF).	[25]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Protein AATF (AATF).	[26]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Protein AATF (AATF).	[29]

6 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Protein AATF (AATF).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Protein AATF (AATF).	[20]
Selenium	DM25CGV	Approved	Selenium increases the expression of Protein AATF (AATF).	[21]
APR-246	DMNFADH	Phase 2	APR-246 increases the expression of Protein AATF (AATF).	[24]
PF-3758309	DM36PKZ	Phase 1	PF-3758309 decreases the expression of Protein AATF (AATF).	[27]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Protein AATF (AATF).	[28]

References

• [1] AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer.Oncogene. 2018 Mar;37(11):1503-1518. doi: 10.1038/s41388-017-0054-6. Epub 2018 Jan 11.
• [2] Cross-interaction of tau PET tracers with monoamine oxidase B: evidence from in silico modelling and in vivo imaging.Eur J Nucl Med Mol Imaging. 2019 Jun;46(6):1369-1382. doi: 10.1007/s00259-019-04305-8. Epub 2019 Mar 27.
• [3] Biological Assessment of a (18)F-Labeled Sulforhodamine 101 in a Mouse Model of Alzheimer's Disease as a Potential Astrocytosis Marker.Front Neurosci. 2019 Jul 16;13:734. doi: 10.3389/fnins.2019.00734. eCollection 2019.
• [4] Air Pollutants are associated with Dry Eye Disease in Urban Ophthalmic Outpatients: a Prevalence Study in China.J Transl Med. 2019 Feb 15;17(1):46. doi: 10.1186/s12967-019-1794-6.
• [5] Che-1 gene silencing induces osteosarcoma cell apoptosis by inhibiting mutant p53 expression.Biochem Biophys Res Commun. 2016 Apr 22;473(1):168-173. doi: 10.1016/j.bbrc.2016.03.073. Epub 2016 Mar 21.
• [6] Che-1 arrests human colon carcinoma cell proliferation by displacing HDAC1 from the p21WAF1/CIP1 promoter.J Biol Chem. 2003 Sep 19;278(38):36496-504. doi: 10.1074/jbc.M306694200. Epub 2003 Jul 7.
• [7] AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis.EMBO J. 2012 Oct 17;31(20):3961-75. doi: 10.1038/emboj.2012.236. Epub 2012 Aug 21.
• [8] A Regulatory Role of Apoptosis Antagonizing Transcription Factor in the Pathogenesis of Nonalcoholic Fatty Liver Disease and Hepatocellular Carcinoma.Hepatology. 2019 Apr;69(4):1520-1534. doi: 10.1002/hep.30346. Epub 2019 Mar 4.
• [9] Che-1 attenuates hypoxia/reoxygenation-induced cardiomyocyte apoptosis by upregulation of Nrf2 signaling.Eur Rev Med Pharmacol Sci. 2018 Feb;22(4):1084-1093. doi: 10.26355/eurrev_201802_14395.
• [10] The PI3K/AKT axis modulates AATF activity in Wilms' tumor cells.FEBS Open Bio. 2018 Sep 4;8(10):1615-1623. doi: 10.1002/2211-5463.12500. eCollection 2018 Oct.
• [11] Inactivation of Apoptosis Antagonizing Transcription Factor in tubular epithelial cells induces accumulation of DNA damage and nephronophthisis.Kidney Int. 2019 Apr;95(4):846-858. doi: 10.1016/j.kint.2018.10.034. Epub 2019 Feb 13.
• [12] Link between spermine oxidase and apoptosis antagonizing transcription factor: A new pathway in neuroblastoma.Int J Oncol. 2019 Nov;55(5):1149-1156. doi: 10.3892/ijo.2019.4878. Epub 2019 Sep 13.
• [13] Radiosensitization of Ras-mutated human tumor cells in vitro by the specific EGF receptor antagonist BIBX1382BS.Radiother Oncol. 2005 Feb;74(2):117-29. doi: 10.1016/j.radonc.2004.11.008. Epub 2004 Dec 9.
• [14] Mutation analysis of the AATF gene in breast cancer families.BMC Cancer. 2009 Dec 21;9:457. doi: 10.1186/1471-2407-9-457.
• [15] A subset of chronic lymphocytic leukemia patients display reduced levels of PARP1 expression coupled with a defective irradiation-induced apoptosis.Exp Hematol. 2012 Mar;40(3):197-206.e1. doi: 10.1016/j.exphem.2011.11.005. Epub 2011 Nov 23.
• [16] Oesophageal atresia with tracheoesophageal fistula and anal atresia in a patient with a de novo microduplication in 17q12.Eur J Med Genet. 2014 Jan;57(1):40-3. doi: 10.1016/j.ejmg.2013.10.007. Epub 2013 Nov 12.
• [17] A clinical utility assessment of the automatic measurement method of the quality of Meibomian glands.Biomed Eng Online. 2017 Jun 24;16(1):82. doi: 10.1186/s12938-017-0373-4.
• [18] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [19] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [20] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [21] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [22] Poly(ADP-ribosyl)ation of Apoptosis Antagonizing Transcription Factor Involved in Hydroquinone-Induced DNA Damage Response. Biomed Environ Sci. 2016 Jan;29(1):80-4. doi: 10.3967/bes2016.008.
• [23] Phosphoproteomics reveals resveratrol-dependent inhibition of Akt/mTORC1/S6K1 signaling. J Proteome Res. 2014 Dec 5;13(12):5734-42. doi: 10.1021/pr500714a. Epub 2014 Oct 29.
• [24] Mutant p53 reactivation by PRIMA-1MET induces multiple signaling pathways converging on apoptosis. Oncogene. 2010 Mar 4;29(9):1329-38. doi: 10.1038/onc.2009.425. Epub 2009 Nov 30.
• [25] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [26] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [27] Inhibition of neuroblastoma proliferation by PF-3758309, a small-molecule inhibitor that targets p21-activated kinase 4. Oncol Rep. 2017 Nov;38(5):2705-2716. doi: 10.3892/or.2017.5989. Epub 2017 Sep 22.
• [28] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [29] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.