Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCBT1A1)

• DOT Name: Progesterone-induced-blocking factor 1 (PIBF1)
• Synonyms: PIBF; Centrosomal protein of 90 kDa; CEP90
• Gene Name: PIBF1
• Related Disease:
  Joubert syndrome 33
  Breast neoplasm
  Gastric cancer
  Joubert syndrome 1
  Neoplasm
  Stomach cancer
  Ciliopathy
  Joubert syndrome
  Breast cancer
  Breast carcinoma
• UniProt ID: PIBF1_HUMAN
• Sequence:
  MSRKISKESKKVNISSSLESEDISLETTVPTDDISSSEEREGKVRITRQLIERKELLHNI
  QLLKIELSQKTMMIDNLKVDYLTKIEELEEKLNDALHQKQLLTLRLDNQLAFQQKDASKY
  QELMKQEMETILLRQKQLEETNLQLREKAGDVRRNLRDFELTEEQYIKLKAFPEDQLSIP
  EYVSVRFYELVNPLRKEICELQVKKNILAEELSTNKNQLKQLTETYEEDRKNYSEVQIRC
  QRLALELADTKQLIQQGDYRQENYDKVKSERDALEQEVIELRRKHEILEASHMIQTKERS
  ELSKEVVTLEQTVTLLQKDKEYLNRQNMELSVRCAHEEDRLERLQAQLEESKKAREEMYE
  KYVASRDHYKTEYENKLHDELEQIRLKTNQEIDQLRNASREMYERENRNLREARDNAVAE
  KERAVMAEKDALEKHDQLLDRYRELQLSTESKVTEFLHQSKLKSFESERVQLLQEETARN
  LTQCQLECEKYQKKLEVLTKEFYSLQASSEKRITELQAQNSEHQARLDIYEKLEKELDEI
  IMQTAEIENEDEAERVLFSYGYGANVPTTAKRRLKQSVHLARRVLQLEKQNSLILKDLEH
  RKDQVTQLSQELDRANSLLNQTQQPYRYLIESVRQRDSKIDSLTESIAQLEKDVSNLNKE
  KSALLQTKNQMALDLEQLLNHREELAAMKQILVKMHSKHSENSLLLTKTEPKHVTENQKS
  KTLNVPKEHEDNIFTPKPTLFTKKEAPEWSKKQKMKT
• Function: Plays a role in ciliogenesis; [Isoform 1]: Pericentriolar protein required to maintain mitotic spindle pole integrity. Required for the centrosomal accumulation of PCM1 and the recruitment of centriolar satellite proteins such as BBS4. Via association with PCM1 may be involved in primary cilia formation. Required for CEP63 centrosomal localization and its interaction with WDR62. Together with CEP63 promotes centriole duplication. Promotes the centrosomal localization of CDK2 ; [Isoform 4]: The secreted form is a mediator of progesterone that by acting on the phospholipase A2 enzyme interferes with arachidonic acid metabolism, induces a Th2 biased immune response, and by controlling decidual naturakl killer cells (NK) activity exerts an anti-abortive effect. Increases the production of Th2-type cytokines by signaling via the JAK/STAT pathway. Activates STAT6 and inhibits STAT4 phosphorylation. Signaling via a not identified receptor seems to implicate IL4R and a GPI-anchored protein.
• Tissue Specificity: Expressed at highest levels in testis. Moderate expression is detected in spleen, thymus, prostate, ovary, small intestine, and colon . Expressed in the first trimester pregnancy decidua . Localized to extravillous cytotrophoblast (at protein level). Also found in syncytiotrophoblast and part of the villous cytotrophoblast. Isoform 1 is expressed in first trimester and term villous trophoblast; trophoblast cells can additionally express other isoforms . Overexpressed in solid tumors from stomach and uterus and in cells from ovary, cervical, breast, lymphoma and leukemia cancer .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Joubert syndrome 33	DISGO990	Definitive	Autosomal recessive	[1]
Breast neoplasm	DISNGJLM	Strong	Altered Expression	[2]
Gastric cancer	DISXGOUK	Strong	Biomarker	[3]
Joubert syndrome 1	DISC9Q82	Strong	GermlineCausalMutation	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Stomach cancer	DISKIJSX	Strong	Biomarker	[3]
Ciliopathy	DIS10G4I	Moderate	Autosomal recessive	[4]
Joubert syndrome	DIS7P5CO	Supportive	Autosomal recessive	[1]
Breast cancer	DIS7DPX1	Disputed	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Disputed	Genetic Variation	[5]

3 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 Progesterone-induced-blocking factor 1 (PIBF1).	[6]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Progesterone-induced-blocking factor 1 (PIBF1).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Progesterone-induced-blocking factor 1 (PIBF1).	[15]

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 Progesterone-induced-blocking factor 1 (PIBF1).	[7]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[8]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[9]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[10]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[12]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[12]
Dydrogesterone	DMAKIDV	Approved	Dydrogesterone increases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[13]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Progesterone-induced-blocking factor 1 (PIBF1).	[14]

References

• [1] An siRNA-based functional genomics screen for the?identification of regulators of ciliogenesis and ciliopathy?genes. Nat Cell Biol. 2015 Aug;17(8):1074-1087. doi: 10.1038/ncb3201. Epub 2015 Jul 13.
• [2] PIBF (progesterone induced blocking factor) is overexpressed in highly proliferating cells and associated with the centrosome.Int J Cancer. 2004 Oct 20;112(1):51-60. doi: 10.1002/ijc.20326.
• [3] MicroRNA-203 suppresses gastric cancer growth by targeting PIBF1/Akt signaling.J Exp Clin Cancer Res. 2016 Mar 15;35:47. doi: 10.1186/s13046-016-0323-1.
• [4] 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.
• [5] The effect of the Progesterone-Induced Blocking Factor (PIBF) on E-cadherin expression, cell motility and invasion of primary tumour cell lines.J Reprod Immunol. 2018 Feb;125:8-15. doi: 10.1016/j.jri.2017.10.047. Epub 2017 Nov 2.
• [6] 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.
• [7] 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.
• [8] 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.
• [9] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [10] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [11] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [12] Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone. Leuk Lymphoma. 2007 Aug;48(8):1610-7. doi: 10.1080/10428190701471999.
• [13] Modulation of cytokine production by dydrogesterone in lymphocytes from women with recurrent miscarriage. BJOG. 2005 Aug;112(8):1096-101. doi: 10.1111/j.1471-0528.2005.00633.x.
• [14] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [15] 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.