Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC0Q2QS)

• DOT Name: CDK5 regulatory subunit-associated protein 3 (CDK5RAP3)
• Synonyms: CDK5 activator-binding protein C53; LXXLL/leucine-zipper-containing ARF-binding protein; Protein HSF-27
• Gene Name: CDK5RAP3
• Related Disease:
  Colon adenocarcinoma
  Colon cancer
  Colon carcinoma
  Colorectal carcinoma
  Hepatocellular carcinoma
  Acute respiratory failure
  Cardiac failure
  Colonic neoplasm
  Congestive heart failure
  Neoplasm
  Rheumatic fever
  Type-1/2 diabetes
  Kidney cancer
  Renal carcinoma
  Adenocarcinoma
• UniProt ID: CK5P3_HUMAN
• Pfam ID: PF05600
• Sequence:
  MEDHQHVPIDIQTSKLLDWLVDRRHCSLKWQSLVLTIREKINAAIQDMPESEEIAQLLSG
  SYIHYFHCLRILDLLKGTEASTKNIFGRYSSQRMKDWQEIIALYEKDNTYLVELSSLLVR
  NVNYEIPSLKKQIAKCQQLQQEYSRKEEECQAGAAEMREQFYHSCKQYGITGENVRGELL
  ALVKDLPSQLAEIGAAAQQSLGEAIDVYQASVGFVCESPTEQVLPMLRFVQKRGNSTVYE
  WRTGTEPSVVERPHLEELPEQVAEDAIDWGDFGVEAVSEGTDSGISAEAAGIDWGIFPES
  DSKDPGGDGIDWGDDAVALQITVLEAGTQAPEGVARGPDALTLLEYTETRNQFLDELMEL
  EIFLAQRAVELSEEADVLSVSQFQLAPAILQGQTKEKMVTMVSVLEDLIGKLTSLQLQHL
  FMILASPRYVDRVTEFLQQKLKQSQLLALKKELMVQKQQEALEEQAALEPKLDLLLEKTK
  ELQKLIEADISKRYSGRPVNLMGTSL
• Function: Substrate adapter for ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, in response to endoplasmic reticulum stress. Negatively regulates NF-kappa-B-mediated gene transcription through the control of RELA phosphorylation. Probable tumor suppressor initially identified as a CDK5R1 interactor controlling cell proliferation. Also regulates mitotic G2/M transition checkpoint and mitotic G2 DNA damage checkpoint. Through its interaction with CDKN2A/ARF and MDM2 may induce MDM2-dependent p53/TP53 ubiquitination, stabilization and activation in the nucleus, thereby promoting G1 cell cycle arrest and inhibition of cell proliferation. May also play a role in the rupture of the nuclear envelope during apoptosis. May regulate MAPK14 activity by regulating its dephosphorylation by PPM1D/WIP1. Required for liver development; (Microbial infection) May be negatively regulated by hepatitis B virus large envelope protein mutant pre-s2 to promote mitotic entry.
• Tissue Specificity: Ubiquitously expressed . Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 3 is expressed in kidney, liver, skeletal muscle and placenta .

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Colon adenocarcinoma	DISDRE0J	Definitive	Altered Expression	[1]
Colon cancer	DISVC52G	Definitive	Genetic Variation	[1]
Colon carcinoma	DISJYKUO	Definitive	Genetic Variation	[1]
Colorectal carcinoma	DIS5PYL0	Definitive	Genetic Variation	[1]
Hepatocellular carcinoma	DIS0J828	Definitive	Biomarker	[2]
Acute respiratory failure	DIS5KQ5Y	Strong	Biomarker	[2]
Cardiac failure	DISDC067	Strong	Altered Expression	[3]
Colonic neoplasm	DISSZ04P	Strong	Altered Expression	[4]
Congestive heart failure	DIS32MEA	Strong	Altered Expression	[3]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Rheumatic fever	DISLUF66	Strong	Biomarker	[2]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[6]
Kidney cancer	DISBIPKM	moderate	Biomarker	[7]
Renal carcinoma	DISER9XT	moderate	Biomarker	[7]
Adenocarcinoma	DIS3IHTY	Limited	Biomarker	[8]

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 CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[12]
Troglitazone	DM3VFPD	Approved	Troglitazone decreases the expression of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[13]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the expression of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[14]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of CDK5 regulatory subunit-associated protein 3 (CDK5RAP3).	[16]

References

• [1] A functional variant of IC53 correlates with the late onset of colorectal cancer.Mol Med. 2011;17(7-8):607-18. doi: 10.2119/molmed.2010.00192. Epub 2011 Mar 2.
• [2] CDK5RAP3 is a novel repressor of p14ARF in hepatocellular carcinoma cells.PLoS One. 2012;7(7):e42210. doi: 10.1371/journal.pone.0042210. Epub 2012 Jul 31.
• [3] A novel gene IC53 stimulates ECV304 cell proliferation and is upregulated in failing heart.Biochem Biophys Res Commun. 2002 May 31;294(1):161-6. doi: 10.1016/S0006-291X(02)00446-1.
• [4] CDK5 is a novel regulatory protein in PPARgamma ligand-induced antiproliferation.Int J Oncol. 2006 Jan;28(1):191-4.
• [5] Overexpression of IC53d promotes the proliferation of gastric cancer cells by activating the AKT/GSK3/cyclinD1 signaling pathway.Oncol Rep. 2019 May;41(5):2739-2752. doi: 10.3892/or.2019.7042. Epub 2019 Mar 5.
• [6] Ubiquitin fold modifier 1 activates NF-B pathway by down-regulating LZAP expression in the macrophage of diabetic mouse model.Biosci Rep. 2020 Jan 31;40(1):BSR20191672. doi: 10.1042/BSR20191672.
• [7] CDK5RAP3 Participates in Autophagy Regulation and Is Downregulated in Renal Cancer.Dis Markers. 2019 Apr 2;2019:6171782. doi: 10.1155/2019/6171782. eCollection 2019.
• [8] Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma.Int J Biol Markers. 2007 Apr-Jun;22(2):108-13. doi: 10.1177/172460080702200204.
• [9] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [14] 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.
• [15] Chemical stresses fail to mimic the unfolded protein response resulting from luminal load with unfolded polypeptides. J Biol Chem. 2018 Apr 13;293(15):5600-5612.
• [16] 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.