Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT02TZ4S)

• DOT Name: Death domain-containing protein CRADD (CRADD)
• Synonyms: Caspase and RIP adapter with death domain; RIP-associated protein with a death domain
• Gene Name: CRADD
• Related Disease:
  Syndromic intellectual disability
  Alzheimer disease
  Amyloidosis
  Bone osteosarcoma
  Clear cell renal carcinoma
  Intellectual disability
  Intellectual disability, autosomal recessive 34
  Knee osteoarthritis
  Lissencephaly spectrum disorders
  Mantle cell lymphoma
  Neoplasm
  Osteoarthritis
  Osteosarcoma
  Papillary renal cell carcinoma
  Renal cell carcinoma
  Megalencephaly
  Autosomal recessive non-syndromic intellectual disability
  Acute myelogenous leukaemia
• UniProt ID: CRADD_HUMAN
• PDB ID: 2O71; 2OF5; 3CRD
• Pfam ID: PF00619 ; PF00531
• Sequence:
  MEARDKQVLRSLRLELGAEVLVEGLVLQYLYQEGILTENHIQEINAQTTGLRKTMLLLDI
  LPSRGPKAFDTFLDSLQEFPWVREKLKKAREEAMTDLPAGDRLTGIPSHILNSSPSDRQI
  NQLAQRLGPEWEPMVLSLGLSQTDIYRCKANHPHNVQSQVVEAFIRWRQRFGKQATFQSL
  HNGLRAVEVDPSLLLHMLE
• Function: Adapter protein that associates with PIDD1 and the caspase CASP2 to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis. Also recruits CASP2 to the TNFR-1 signaling complex through its interaction with RIPK1 and TRADD and may play a role in the tumor necrosis factor-mediated signaling pathway.
• Tissue Specificity: Constitutively expressed in most tissues, with particularly high expression in adult heart, testis, liver, skeletal muscle, fetal liver and kidney.
• Reactome Pathway: TP53 Regulates Transcription of Caspase Activators and Caspases (R-HSA-6803207)
• BioCyc Pathway: MetaCyc:ENSG00000169372-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

18 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Syndromic intellectual disability	DISH7SDF	Definitive	Autosomal recessive	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
Bone osteosarcoma	DIST1004	Strong	Altered Expression	[4]
Clear cell renal carcinoma	DISBXRFJ	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Intellectual disability, autosomal recessive 34	DISTSM1A	Strong	Autosomal recessive	[7]
Knee osteoarthritis	DISLSNBJ	Strong	Genetic Variation	[8]
Lissencephaly spectrum disorders	DISBCZL7	Strong	Genetic Variation	[6]
Mantle cell lymphoma	DISFREOV	Strong	Genetic Variation	[9]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[10]
Osteoarthritis	DIS05URM	Strong	Genetic Variation	[8]
Osteosarcoma	DISLQ7E2	Strong	Altered Expression	[4]
Papillary renal cell carcinoma	DIS25HBV	Strong	Biomarker	[5]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[5]
Megalencephaly	DISYW5SV	moderate	Genetic Variation	[3]
Autosomal recessive non-syndromic intellectual disability	DISJWRZZ	Supportive	Autosomal recessive	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Death domain-containing protein CRADD (CRADD).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Death domain-containing protein CRADD (CRADD).	[13]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Death domain-containing protein CRADD (CRADD).	[14]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Death domain-containing protein CRADD (CRADD).	[15]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Death domain-containing protein CRADD (CRADD).	[16]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Death domain-containing protein CRADD (CRADD).	[17]
Beta-carotene	DM0RXBT	Approved	Beta-carotene increases the expression of Death domain-containing protein CRADD (CRADD).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate decreases the expression of Death domain-containing protein CRADD (CRADD).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Death domain-containing protein CRADD (CRADD).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Death domain-containing protein CRADD (CRADD).	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Death domain-containing protein CRADD (CRADD).	[21]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] Genome-wide association study of the rate of cognitive decline in Alzheimer's disease.Alzheimers Dement. 2014 Jan;10(1):45-52. doi: 10.1016/j.jalz.2013.01.008. Epub 2013 Mar 25.
• [3] Mutations in CRADD Result in Reduced Caspase-2-Mediated Neuronal Apoptosis and Cause Megalencephaly with a Rare Lissencephaly Variant. Am J Hum Genet. 2016 Nov 3;99(5):1117-1129. doi: 10.1016/j.ajhg.2016.09.010. Epub 2016 Oct 20.
• [4] RAIDD expression is impaired in multidrug resistant osteosarcoma cell lines.Cancer Chemother Pharmacol. 2009 Aug;64(3):607-14. doi: 10.1007/s00280-008-0912-6. Epub 2009 Jan 6.
• [5] PIDDosome expression and the role of caspase-2 activation for chemotherapy-induced apoptosis in RCCs.Cell Oncol. 2010;32(1-2):29-42. doi: 10.3233/CLO-2009-0492.
• [6] Phenotypic spectrum associated with a CRADD founder variant underlying frontotemporal predominant pachygyria in the Finnish population.Eur J Hum Genet. 2019 Aug;27(8):1235-1243. doi: 10.1038/s41431-019-0383-8. Epub 2019 Mar 26.
• [7] Genetic mapping and exome sequencing identify variants associated with five novel diseases. PLoS One. 2012;7(1):e28936. doi: 10.1371/journal.pone.0028936. Epub 2012 Jan 17.
• [8] Identification of new therapeutic targets for osteoarthritis through genome-wide analyses of UK Biobank data. Nat Genet. 2019 Feb;51(2):230-236.
• [9] Altered apoptosis pathways in mantle cell lymphoma detected by oligonucleotide microarray.Blood. 2001 Aug 1;98(3):787-94. doi: 10.1182/blood.v98.3.787.
• [10] Genetic heterogeneity in leiomyomas of deep soft tissue.Oncotarget. 2017 Jul 25;8(30):48769-48781. doi: 10.18632/oncotarget.17953.
• [11] Identification of novel genes with prognostic value in childhood leukemia using cDNA microarray and quantitative RT-PCR.Pediatr Hematol Oncol. 2006 Mar;23(2):115-27. doi: 10.1080/08880010500457780.
• [12] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [15] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [16] Quercetin and Its Fermented Extract as a Potential Inhibitor of Bisphenol A-Exposed HT-29 Colon Cancer Cells' Viability. Int J Mol Sci. 2023 Mar 15;24(6):5604. doi: 10.3390/ijms24065604.
• [17] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [18] Beta-carotene and apocarotenals promote retinoid signaling in BEAS-2B human bronchioepithelial cells. Arch Biochem Biophys. 2006 Nov 1;455(1):48-60.
• [19] Molecular mechanisms of action of angiopreventive anti-oxidants on endothelial cells: microarray gene expression analyses. Mutat Res. 2005 Dec 11;591(1-2):198-211.
• [20] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [21] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [22] Identification of genes associated with paraquat-induced toxicity in SH-SY5Y cells by PCR array focused on apoptotic pathways. J Toxicol Environ Health A. 2008;71(22):1457-67. doi: 10.1080/15287390802329364.