Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFE2ELA)

• DOT Name: Protein fem-1 homolog B (FEM1B)
• Synonyms: FEM1b; FEM1-beta; Fem-1-like death receptor-binding protein alpha; Fem-1-like in apoptotic pathway protein alpha; F1A-alpha
• Gene Name: FEM1B
• Related Disease:
  T-cell acute lymphoblastic leukaemia
  Bardet biedl syndrome
  Colon cancer
  Colon carcinoma
  Non-insulin dependent diabetes
  Polycystic ovarian syndrome
  Intellectual disability
  Neurodevelopmental disorder
• UniProt ID: FEM1B_HUMAN
• PDB ID: 6LBF; 7CNG; 7EL6
• Pfam ID: PF00023 ; PF12796
• Sequence:
  MEGLAGYVYKAASEGKVLTLAALLLNRSESDIRYLLGYVSQQGGQRSTPLIIAARNGHAK
  VVRLLLEHYRVQTQQTGTVRFDGYVIDGATALWCAAGAGHFEVVKLLVSHGANVNHTTVT
  NSTPLRAACFDGRLDIVKYLVENNANISIANKYDNTCLMIAAYKGHTDVVRYLLEQRADP
  NAKAHCGATALHFAAEAGHIDIVKELIKWRAAIVVNGHGMTPLKVAAESCKADVVELLLS
  HADCDRRSRIEALELLGASFANDRENYDIIKTYHYLYLAMLERFQDGDNILEKEVLPPIH
  AYGNRTECRNPQELESIRQDRDALHMEGLIVRERILGADNIDVSHPIIYRGAVYADNMEF
  EQCIKLWLHALHLRQKGNRNTHKDLLRFAQVFSQMIHLNETVKAPDIECVLRCSVLEIEQ
  SMNRVKNISDADVHNAMDNYECNLYTFLYLVCISTKTQCSEEDQCKINKQIYNLIHLDPR
  TREGFTLLHLAVNSNTPVDDFHTNDVCSFPNALVTKLLLDCGAEVNAVDNEGNSALHIIV
  QYNRPISDFLTLHSIIISLVEAGAHTDMTNKQNKTPLDKSTTGVSEILLKTQMKMSLKCL
  AARAVRANDINYQDQIPRTLEEFVGFH
• Function: Substrate-recognition component of a Cul2-RING (CRL2) E3 ubiquitin-protein ligase complex of the DesCEND (destruction via C-end degrons) pathway, which recognizes a C-degron located at the extreme C terminus of target proteins, leading to their ubiquitination and degradation. The C-degron recognized by the DesCEND pathway is usually a motif of less than ten residues and can be present in full-length proteins, truncated proteins or proteolytically cleaved forms. The CRL2(FEM1B) complex specifically recognizes proteins ending with -Gly-Leu-Asp-Arg, such as CDK5R1, leading to their ubiquitination and degradation. Also acts as a regulator of the reductive stress response by mediating ubiquitination of reduced FNIP1: in response to reductive stress, the CRL2(FEM1B) complex specifically recognizes a conserved Cys degron in FNIP1 when this degron is reduced, leading to FNIP1 degradation and subsequent activation of mitochondria to recalibrate reactive oxygen species (ROS). Mechanistically, recognizes and binds reduced FNIP1 through two interface zinc ions, which act as a molecular glue that recruit reduced FNIP1 to FEM1B. Promotes ubiquitination of GLI1, suppressing GLI1 transcriptional activator activity. Promotes ubiquitination and degradation of ANKRD37. Promotes ubiquitination and degradation of SLBP. Involved in apoptosis by acting as a death receptor-associated protein that mediates apoptosis. Also involved in glucose homeostasis in pancreatic islet. May also act as an adapter/mediator in replication stress-induced signaling that leads to the activation of CHEK1.
• Tissue Specificity: Widely expressed . Highly expressed in testis . Weakly expressed in other tissues .
• 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
T-cell acute lymphoblastic leukaemia	DIS17AI2	Definitive	Altered Expression	[1]
Bardet biedl syndrome	DISTBNZW	Strong	Biomarker	[2]
Colon cancer	DISVC52G	Strong	Altered Expression	[3]
Colon carcinoma	DISJYKUO	Strong	Altered Expression	[3]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[4]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Genetic Variation	[5]
Intellectual disability	DISMBNXP	Limited	Biomarker	[6]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[6]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Protein fem-1 homolog B (FEM1B).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Protein fem-1 homolog B (FEM1B).	[14]

9 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 Protein fem-1 homolog B (FEM1B).	[8]
Doxorubicin	DMVP5YE	Approved	Doxorubicin affects the expression of Protein fem-1 homolog B (FEM1B).	[9]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Protein fem-1 homolog B (FEM1B).	[10]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Protein fem-1 homolog B (FEM1B).	[11]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of Protein fem-1 homolog B (FEM1B).	[12]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Protein fem-1 homolog B (FEM1B).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Protein fem-1 homolog B (FEM1B).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Protein fem-1 homolog B (FEM1B).	[16]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Protein fem-1 homolog B (FEM1B).	[17]

References

• [1] Increased PKC activity by Rack1 overexpression is responsible for chemotherapy resistance in T-cell acute lymphoblastic leukemia-derived cell line.Sci Rep. 2016 Sep 20;6:33717. doi: 10.1038/srep33717.
• [2] Rapid communication: the human FEM1B gene maps to chromosome 15q22 and is excluded as the gene for Bardet-Biedl syndrome, type 4.Am J Med Sci. 2000 Apr;319(4):268-70. doi: 10.1097/00000441-200004000-00014.
• [3] RACK1 downregulates levels of the pro-apoptotic protein Fem1b in apoptosis-resistant colon cancer cells.Cancer Biol Ther. 2009 Dec;8(23):2297-305. doi: 10.4161/cbt.8.23.10262. Epub 2009 Dec 7.
• [4] Abnormal glucose homeostasis and pancreatic islet function in mice with inactivation of the Fem1b gene.Mol Cell Biol. 2005 Aug;25(15):6570-7. doi: 10.1128/MCB.25.15.6570-6577.2005.
• [5] FEM1A and FEM1B: novel candidate genes for polycystic ovary syndrome.Hum Reprod. 2008 Dec;23(12):2842-9. doi: 10.1093/humrep/den324. Epub 2008 Aug 29.
• [6] Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants.Genet Med. 2019 Nov;21(11):2504-2511. doi: 10.1038/s41436-019-0518-x. Epub 2019 Apr 30.
• [7] 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.
• [8] 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.
• [9] 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.
• [10] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [11] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [12] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [13] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [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] 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.
• [16] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.
• [17] The contact allergen nickel triggers a unique inflammatory and proangiogenic gene expression pattern via activation of NF-kappaB and hypoxia-inducible factor-1alpha. J Immunol. 2007 Mar 1;178(5):3198-207.