Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTXNW3P6)

• DOT Name: Cornifin-B (SPRR1B)
• Synonyms: 14.9 kDa pancornulin; Small proline-rich protein IB; SPR-IB
• Gene Name: SPRR1B
• Related Disease:
  Adenocarcinoma
  Craniosynostosis
  Lung adenocarcinoma
  Skin disease
  Graft-versus-host disease
  Keratoconjunctivitis sicca
  Large cell carcinoma
  Sjogren syndrome
• UniProt ID: SPR1B_HUMAN
• Pfam ID: PF02389
• Sequence:
  MSSQQQKQPCTPPPQLQQQQVKQPCQPPPQEPCIPKTKEPCHPKVPEPCHPKVPEPCQPK
  VPEPCHPKVPEPCPSIVTPAPAQQKTKQK
• Function: Cross-linked envelope protein of keratinocytes. It is a keratinocyte protein that first appears in the cell cytosol, but ultimately becomes cross-linked to membrane proteins by transglutaminase. All that results in the formation of an insoluble envelope beneath the plasma membrane. Can function as both amine donor and acceptor in transglutaminase-mediated cross-linkage.
• Tissue Specificity: Suprabasal layers of squamous-differentiated tissues such as epidermis, esophagus, tongue and trachea.
• Reactome Pathway: Formation of the cornified envelope (R-HSA-6809371)

Molecular Interaction Atlas (MIA) of This DOT

8 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[1]
Craniosynostosis	DIS6J405	Strong	Biomarker	[2]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[1]
Skin disease	DISDW8R6	Strong	Altered Expression	[3]
Graft-versus-host disease	DIS0QADF	Limited	Biomarker	[4]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[5]
Large cell carcinoma	DISYMCOF	Limited	Altered Expression	[6]
Sjogren syndrome	DISUBX7H	Limited	Altered Expression	[5]

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 Cornifin-B (SPRR1B).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Cornifin-B (SPRR1B).	[15]

9 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Cornifin-B (SPRR1B).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Cornifin-B (SPRR1B).	[9]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Cornifin-B (SPRR1B).	[10]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil affects the expression of Cornifin-B (SPRR1B).	[11]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Cornifin-B (SPRR1B).	[12]
Isotretinoin	DM4QTBN	Approved	Isotretinoin increases the expression of Cornifin-B (SPRR1B).	[13]
Alitretinoin	DMME8LH	Approved	Alitretinoin decreases the expression of Cornifin-B (SPRR1B).	[13]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Cornifin-B (SPRR1B).	[14]
all-trans-4-oxo-retinoic acid	DMM2R1N	Investigative	all-trans-4-oxo-retinoic acid decreases the expression of Cornifin-B (SPRR1B).	[13]

References

• [1] SPRR1B overexpression enhances entry of cells into the G0 phase of the cell cycle.Am J Physiol Lung Cell Mol Physiol. 2003 Oct;285(4):L889-98. doi: 10.1152/ajplung.00065.2003. Epub 2003 Jun 27.
• [2] RNA sequencing and pathway analysis identify tumor necrosis factor alpha driven small proline-rich protein dysregulation in chronic rhinosinusitis.Am J Rhinol Allergy. 2017 Sep 1;31(5):283-288. doi: 10.2500/ajra.2017.31.4457.
• [3] Differential expression of human cornifin alpha and beta in squamous differentiating epithelial tissues and several skin lesions.J Invest Dermatol. 1997 Feb;108(2):200-4. doi: 10.1111/1523-1747.ep12334240.
• [4] Subconjunctival injection of mesenchymal stromal cells protects the cornea in an experimental model of GVHD.Ocul Surf. 2019 Apr;17(2):285-294. doi: 10.1016/j.jtos.2019.01.001. Epub 2019 Jan 8.
• [5] Small proline-rich protein 1B (SPRR1B) is a biomarker for squamous metaplasia in dry eye disease.Invest Ophthalmol Vis Sci. 2008 Jan;49(1):34-41. doi: 10.1167/iovs.07-0685.
• [6] Mechanism of repression of squamous differentiation marker, SPRR1B, in malignant bronchial epithelial cells: role of critical TRE-sites and its transacting factors.Oncogene. 2001 Feb 1;20(5):634-44. doi: 10.1038/sj.onc.1204134.
• [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] Evaluation of a human iPSC-derived BBB model for repeated dose toxicity testing with cyclosporine A as model compound. Toxicol In Vitro. 2021 Jun;73:105112. doi: 10.1016/j.tiv.2021.105112. Epub 2021 Feb 22.
• [9] Retinoic acid receptors as regulators of human epidermal keratinocyte differentiation. Mol Endocrinol. 1992 May;6(5):667-76. doi: 10.1210/mend.6.5.1318502.
• [10] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [11] Multi-level gene expression profiles affected by thymidylate synthase and 5-fluorouracil in colon cancer. BMC Genomics. 2006 Apr 3;7:68. doi: 10.1186/1471-2164-7-68.
• [12] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [13] Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. J Invest Dermatol. 2005 Jul;125(1):143-53.
• [14] Keratinocyte differentiation marker suppression by arsenic: mediation by AP1 response elements and antagonism by tetradecanoylphorbol acetate. Toxicol Appl Pharmacol. 2001 Aug 1;174(3):302-11.
• [15] 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.