Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT87CYMW)

• DOT Name: Tubby-related protein 3
• Synonyms: Tubby-like protein 3
• Gene Name: TULP3
• Related Disease:
  Ciliopathy
  Hepatorenocardiac degenerative fibrosis
• UniProt ID: TULP3_HUMAN
• PDB ID: 8FH3
• Pfam ID: PF01167 ; PF16322
• Sequence:
  MEASRCRLSPSGDSVFHEEMMKMRQAKLDYQRLLLEKRQRKKRLEPFMVQPNPEARLRRA
  KPRASDEQTPLVNCHTPHSNVILHGIDGPAAVLKPDEVHAPSVSSSVVEEDAENTVDTAS
  KPGLQERLQKHDISESVNFDEETDGISQSACLERPNSASSQNSTDTGTSGSATAAQPADN
  LLGDIDDLEDFVYSPAPQGVTVRCRIIRDKRGMDRGLFPTYYMYLEKEENQKIFLLAARK
  RKKSKTANYLISIDPVDLSREGESYVGKLRSNLMGTKFTVYDRGICPMKGRGLVGAAHTR
  QELAAISYETNVLGFKGPRKMSVIIPGMTLNHKQIPYQPQNNHDSLLSRWQNRTMENLVE
  LHNKAPVWNSDTQSYVLNFRGRVTQASVKNFQIVHKNDPDYIVMQFGRVADDVFTLDYNY
  PLCAVQAFGIGLSSFDSKLACE
• Function: Negative regulator of the Shh signaling transduction pathway: recruited to primary cilia via association with the IFT complex A (IFT-A) and is required for recruitment of G protein-coupled receptor GPR161 to cilia, a promoter of PKA-dependent basal repression machinery in Shh signaling. Binds to phosphorylated inositide (phosphoinositide) lipids. Both IFT-A- and phosphoinositide-binding properties are required to regulate ciliary G protein-coupled receptor trafficking. During adipogenesis, regulates ciliary trafficking of FFAR4 in preadipocytes.
• Tissue Specificity: Expressed at high levels in testis, ovaries, thyroid, and spinal chord.
• Reactome Pathway: Hedgehog 'off' state (R-HSA-5610787)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ciliopathy	DIS10G4I	Strong	Autosomal recessive	[1]
Hepatorenocardiac degenerative fibrosis	DISYOIXT	Strong	Autosomal recessive	[2]

This DOT Affected the Drug Response of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Temozolomide	DMKECZD	Approved	Tubby-related protein 3 affects the response to substance of Temozolomide.	[16]
DTI-015	DMXZRW0	Approved	Tubby-related protein 3 affects the response to substance of DTI-015.	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Tubby-related protein 3.	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Tubby-related protein 3.	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tubby-related protein 3.	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Tubby-related protein 3.	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Tubby-related protein 3.	[7]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tubby-related protein 3.	[8]
Selenium	DM25CGV	Approved	Selenium decreases the expression of Tubby-related protein 3.	[9]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Tubby-related protein 3.	[10]
Tamibarotene	DM3G74J	Phase 3	Tamibarotene affects the expression of Tubby-related protein 3.	[5]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Tubby-related protein 3.	[11]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of Tubby-related protein 3.	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Tubby-related protein 3.	[12]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Tubby-related protein 3.	[13]
geraniol	DMS3CBD	Investigative	geraniol increases the expression of Tubby-related protein 3.	[14]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of Tubby-related protein 3.	[15]

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] Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations. Am J Hum Genet. 2022 May 5;109(5):928-943. doi: 10.1016/j.ajhg.2022.03.015. Epub 2022 Apr 8.
• [3] 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.
• [4] 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.
• [5] Differential modulation of PI3-kinase/Akt pathway during all-trans retinoic acid- and Am80-induced HL-60 cell differentiation revealed by DNA microarray analysis. Biochem Pharmacol. 2004 Dec 1;68(11):2177-86.
• [6] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [9] 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.
• [10] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [11] Changes in gene expressions elicited by physiological concentrations of genistein on human endometrial cancer cells. Mol Carcinog. 2006 Oct;45(10):752-63.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Geraniol suppresses prostate cancer growth through down-regulation of E2F8. Cancer Med. 2016 Oct;5(10):2899-2908.
• [15] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [16] Tumor necrosis factor-alpha-induced protein 3 as a putative regulator of nuclear factor-kappaB-mediated resistance to O6-alkylating agents in human glioblastomas. J Clin Oncol. 2006 Jan 10;24(2):274-87. doi: 10.1200/JCO.2005.02.9405. Epub 2005 Dec 19.