Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6R7DXN)

• DOT Name: COMM domain-containing protein 5 (COMMD5)
• Synonyms: Hypertension-related calcium-regulated gene protein; HCaRG
• Gene Name: COMMD5
• Related Disease:
  Nephropathy
  Gastric neoplasm
  High blood pressure
  Non-small-cell lung cancer
  Advanced cancer
  Clear cell renal carcinoma
  Renal cell carcinoma
  Neoplasm
• UniProt ID: COMD5_HUMAN
• PDB ID: 8ESD; 8F2R; 8F2U
• Pfam ID: PF07258 ; PF21672
• Sequence:
  MSAVGAATPYLHHPGDSHSGRVSFLGAQLPPEVAAMARLLGDLDRSTFRKLLKFVVSSLQ
  GEDCREAVQRLGVSANLPEEQLGALLAGMHTLLQQALRLPPTSLKPDTFRDQLQELCIPQ
  DLVGDLASVVFGSQRPLLDSVAQQQGAWLPHVADFRWRVDVAISTSALARSLQPSVLMQL
  KLSDGSAYRFEVPTAKFQELRYSVALVLKEMADLEKRCERRLQD
• Function: May modulate activity of cullin-RING E3 ubiquitin ligase (CRL) complexes. Negatively regulates cell proliferation. Negatively regulates cell cycle G2/M phase transition probably by transactivating p21/CDKN1A through the p53/TP53-independent signaling pathway. Involved in kidney proximal tubule morphogenesis. Down-regulates activation of NF-kappa-B.
• Tissue Specificity: Highly expressed in heart, stomach, jejunum, kidney, liver, and adrenal gland. Expression was generally higher in adult organs than in fetal tissues, particularly in heart, kidney, and liver.
• Reactome Pathway: Neddylation (R-HSA-8951664)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Nephropathy	DISXWP4P	Definitive	Biomarker	[1]
Gastric neoplasm	DISOKN4Y	Strong	Altered Expression	[2]
High blood pressure	DISY2OHH	Strong	Biomarker	[1]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Disputed	Biomarker	[4]
Clear cell renal carcinoma	DISBXRFJ	Disputed	Biomarker	[4]
Renal cell carcinoma	DISQZ2X8	Disputed	Biomarker	[4]
Neoplasm	DISZKGEW	Limited	Altered Expression	[5]

3 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 COMM domain-containing protein 5 (COMMD5).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of COMM domain-containing protein 5 (COMMD5).	[7]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of COMM domain-containing protein 5 (COMMD5).	[2]

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 COMM domain-containing protein 5 (COMMD5).	[9]

References

• [1] Hypertension-related, calcium-regulated gene (HCaRG/COMMD5) and kidney diseases: HCaRG accelerates tubular repair.J Nephrol. 2014 Aug;27(4):351-60. doi: 10.1007/s40620-014-0054-3. Epub 2014 Feb 11.
• [2] Rosiglitazone suppresses gastric carcinogenesis by up-regulating HCaRG expression. Oncol Rep. 2008 Nov;20(5):1093-7.
• [3] COMMD9 promotes TFDP1/E2F1 transcriptional activity via interaction with TFDP1 in non-small cell lung cancer.Cell Signal. 2017 Jan;30:59-66. doi: 10.1016/j.cellsig.2016.11.016. Epub 2016 Nov 19.
• [4] HCaRG/COMMD5 inhibits ErbB receptor-driven renal cell carcinoma.Oncotarget. 2017 May 19;8(41):69559-69576. doi: 10.18632/oncotarget.18012. eCollection 2017 Sep 19.
• [5] HCaRG, a novel calcium-regulated gene coding for a nuclear protein, is potentially involved in the regulation of cell proliferation.J Biol Chem. 2000 Oct 13;275(41):32234-43. doi: 10.1074/jbc.M001352200.
• [6] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [7] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [8] Rosiglitazone suppresses gastric carcinogenesis by up-regulating HCaRG expression. Oncol Rep. 2008 Nov;20(5):1093-7.
• [9] 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.