Details of Drug Off-Target (DOT)

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

• DOT Name: Baculoviral IAP repeat-containing protein 7 (BIRC7)
• Synonyms: EC 2.3.2.27; Kidney inhibitor of apoptosis protein; KIAP; Livin; Melanoma inhibitor of apoptosis protein; ML-IAP; RING finger protein 50; RING-type E3 ubiquitin transferase BIRC7
• Gene Name: BIRC7
• UniProt ID: BIRC7_HUMAN
• PDB ID: 1OXN; 1OXQ; 1OY7; 1TW6; 2I3H; 2I3I; 3F7G; 3F7H; 3F7I; 3GT9; 3GTA; 3UW5; 4AUQ
• EC Number: 2.3.2.27
• Pfam ID: PF00653 ; PF13920
• Sequence:
  MGPKDSAKCLHRGPQPSHWAAGDGPTQERCGPRSLGSPVLGLDTCRAWDHVDGQILGQLR
  PLTEEEEEEGAGATLSRGPAFPGMGSEELRLASFYDWPLTAEVPPELLAAAGFFHTGHQD
  KVRCFFCYGGLQSWKRGDDPWTEHAKWFPSCQFLLRSKGRDFVHSVQETHSQLLGSWDPW
  EEPEDAAPVAPSVPASGYPELPTPRREVQSESAQEPGGVSPAEAQRAWWVLEPPGARDVE
  AQLRRLQEERTCKVCLDRAVSIVFVPCGHLVCAECAPGLQLCPICRAPVRSRVRTFLS
• Function: Apoptotic regulator capable of exerting proapoptotic and anti-apoptotic activities and plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is mediated through the inhibition of CASP3, CASP7 and CASP9, as well as by its E3 ubiquitin-protein ligase activity. As it is a weak caspase inhibitor, its anti-apoptotic activity is thought to be due to its ability to ubiquitinate DIABLO/SMAC targeting it for degradation thereby promoting cell survival. May contribute to caspase inhibition, by blocking the ability of DIABLO/SMAC to disrupt XIAP/BIRC4-caspase interactions. Protects against apoptosis induced by TNF or by chemical agents such as adriamycin, etoposide or staurosporine. Suppression of apoptosis is mediated by activation of MAPK8/JNK1, and possibly also of MAPK9/JNK2. This activation depends on TAB1 and MAP3K7/TAK1. In vitro, inhibits CASP3 and proteolytic activation of pro-CASP9 ; [Isoform 1]: Blocks staurosporine-induced apoptosis. Promotes natural killer (NK) cell-mediated killing ; [Isoform 2]: Blocks etoposide-induced apoptosis. Protects against natural killer (NK) cell-mediated killing.
• Tissue Specificity: Isoform 1 and isoform 2 are expressed at very low levels or not detectable in most adult tissues. Detected in adult heart, placenta, lung, lymph node, spleen and ovary, and in several carcinoma cell lines. Isoform 2 is detected in fetal kidney, heart and spleen, and at lower levels in adult brain, skeletal muscle and peripheral blood leukocytes.
• KEGG Pathway:
  Ubiquitin mediated proteolysis (hsa04120)
  Apoptosis - multiple species (hsa04215)
  Toxoplasmosis (hsa05145)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluorouracil	DMUM7HZ	Approved	Baculoviral IAP repeat-containing protein 7 (BIRC7) decreases the response to substance of Fluorouracil.	[12]
Etoposide	DMNH3PG	Approved	Baculoviral IAP repeat-containing protein 7 (BIRC7) decreases the response to substance of Etoposide.	[12]
Vinblastine	DM5TVS3	Approved	Baculoviral IAP repeat-containing protein 7 (BIRC7) decreases the response to substance of Vinblastine.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[11]

8 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 Baculoviral IAP repeat-containing protein 7 (BIRC7).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[3]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[6]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[7]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[8]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Baculoviral IAP repeat-containing protein 7 (BIRC7).	[9]

References

• [1] 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.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Rapid induction of IAP family proteins and Smac/DIABLO expression after proapoptotic stimulation with doxorubicin in RPMI 8226 multiple myeloma cells. Exp Mol Pathol. 2007 Dec;83(3):405-12. doi: 10.1016/j.yexmp.2007.04.001. Epub 2007 Apr 18.
• [4] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [5] Curcumin reduces the expression of survivin, leading to enhancement of arsenic trioxide-induced apoptosis in myelodysplastic syndrome and leukemia stem-like cells. Oncol Rep. 2016 Sep;36(3):1233-42. doi: 10.3892/or.2016.4944. Epub 2016 Jul 15.
• [6] 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.
• [7] [Effects of bortezomib alone or combined with arsenic trioxide on the apoptosis of Jurkat cells and expression of livin mRNA]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Aug;19(4):898-901.
• [8] Resveratrol at anti-angiogenesis/anticancer concentrations suppresses protein kinase G signaling and decreases IAPs expression in HUVECs. Anticancer Res. 2015 Jan;35(1):273-81.
• [9] Antitumor effects of curcumin, alone or in combination with cisplatin or doxorubicin, on human hepatic cancer cells. Analysis of their possible relationship to changes in NF-kB activation levels and in IAP gene expression. Cancer Lett. 2005 Jun 16;224(1):53-65. doi: 10.1016/j.canlet.2004.10.051.
• [10] 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.
• [11] 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.
• [12] Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis. Cell Mol Life Sci. 2007 May;64(9):1137-44. doi: 10.1007/s00018-007-6510-7.