Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9ZEGV7)

• DOT Name: Calcium-responsive transactivator (SS18L1)
• Synonyms: SS18-like protein 1; SYT homolog 1
• Gene Name: SS18L1
• Related Disease:
  Anorexia nervosa cachexia
  Autoimmune disease
  Bipolar disorder
  Cardiac arrest
  Diffuse systemic sclerosis
  Graves disease
  Roberts-SC phocomelia syndrome
  Synovial sarcoma
  Systemic lupus erythematosus
  Amyotrophic lateral sclerosis
  Amyotrophic lateral sclerosis type 1
  Metastatic malignant neoplasm
  Melanoma
  Primary biliary cholangitis
  Scleroderma
  Stroke
• UniProt ID: CREST_HUMAN
• Pfam ID: PF05030
• Sequence:
  MSVAFASARPRGKGEVTQQTIQKMLDENHHLIQCILEYQSKGKTAECTQYQQILHRNLVY
  LATIADSNQNMQSLLPAPPTQNMNLGPGALTQSGSSQGLHSQGSLSDAISTGLPPSSLLQ
  GQIGNGPSHVSMQQTAPNTLPTTSMSISGPGYSHAGPASQGVPMQGQGTIGNYVSRTNIN
  MQSNPVSMMQQQAATSHYSSAQGGSQHYQGQSSIAMMGQGSQGSSMMGQRPMAPYRPSQQ
  GSSQQYLGQEEYYGEQYSHSQGAAEPMGQQYYPDGHGDYAYQQSSYTEQSYDRSFEESTQ
  HYYEGGNSQYSQQQAGYQQGAAQQQTYSQQQYPSQQSYPGQQQGYGSAQGAPSQYPGYQQ
  GQGQQYGSYRAPQTAPSAQQQRPYGYEQGQYGNYQQ
• Function: Transcriptional activator which is required for calcium-dependent dendritic growth and branching in cortical neurons. Recruits CREB-binding protein (CREBBP) to nuclear bodies. Component of the CREST-BRG1 complex, a multiprotein complex that regulates promoter activation by orchestrating a calcium-dependent release of a repressor complex and a recruitment of an activator complex. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex. At the same time, there is increased recruitment of CREBBP to the promoter by a CREST-dependent mechanism, which leads to transcriptional activation. The CREST-BRG1 complex also binds to the NR2B promoter, and activity-dependent induction of NR2B expression involves a release of HDAC1 and recruitment of CREBBP.
• Tissue Specificity: Ubiquitous; with lowest levels in spleen.
• KEGG Pathway:
  ATP-dependent chromatin remodeling (hsa03082)
  Transcriptio.l misregulation in cancer (hsa05202)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Anorexia nervosa cachexia	DISFO5RQ	Strong	Biomarker	[1]
Autoimmune disease	DISORMTM	Strong	Biomarker	[2]
Bipolar disorder	DISAM7J2	Strong	Biomarker	[3]
Cardiac arrest	DIS9DIA4	Strong	Biomarker	[4]
Diffuse systemic sclerosis	DISYF5LP	Strong	Biomarker	[5]
Graves disease	DISU4KOQ	Strong	Biomarker	[6]
Roberts-SC phocomelia syndrome	DIS4JXZ4	Strong	Biomarker	[7]
Synovial sarcoma	DISEZJS7	Strong	Genetic Variation	[8]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Moderate	Autosomal dominant	[10]
Amyotrophic lateral sclerosis type 1	DIS5A2M0	moderate	Biomarker	[11]
Metastatic malignant neoplasm	DIS86UK6	moderate	Genetic Variation	[12]
Melanoma	DIS1RRCY	Limited	Biomarker	[13]
Primary biliary cholangitis	DIS43E0O	Limited	Biomarker	[14]
Scleroderma	DISVQ342	Limited	Genetic Variation	[15]
Stroke	DISX6UHX	Limited	Biomarker	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Calcium-responsive transactivator (SS18L1).	[17]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Calcium-responsive transactivator (SS18L1).	[18]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of Calcium-responsive transactivator (SS18L1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Calcium-responsive transactivator (SS18L1).	[20]

References

• [1] Effectiveness of emotional skills training for patients with anorexia nervosa with autistic symptoms in group and individual format.Eur Eat Disord Rev. 2018 Jul;26(4):367-375. doi: 10.1002/erv.2594. Epub 2018 Apr 2.
• [2] Familial scleroderma: HLA antigens and autoantibodies.Br J Rheumatol. 1993 Apr;32(4):336-8. doi: 10.1093/rheumatology/32.4.336.
• [3] Bipolar disorder research 2.0: Web technologies for research capacity and knowledge translation.J Eval Clin Pract. 2017 Dec;23(6):1144-1152. doi: 10.1111/jep.12736. Epub 2017 May 4.
• [4] Derivation and Validation of the CREST Model for Very Early Prediction of Circulatory Etiology Death in Patients Without ST-Segment-Elevation Myocardial Infarction After Cardiac Arrest.Circulation. 2018 Jan 16;137(3):273-282. doi: 10.1161/CIRCULATIONAHA.116.024332. Epub 2017 Oct 26.
• [5] DNA-DR typing shows HLA-DRw11 RFLPs are increased in frequency in both progressive systemic sclerosis and CREST variants of scleroderma.Tissue Antigens. 1989 Mar;33(3):418-20. doi: 10.1111/j.1399-0039.1989.tb01686.x.
• [6] Autoantibodies to FK506 binding protein 12 (FKBP12) in autoimmune diseases.Autoimmunity. 1999;29(3):159-70. doi: 10.3109/08916939908998531.
• [7] Roberts syndrome: phenotypic variation, cytogenetic definition and heterozygote detection.Ann Genet. 1991;34(3-4):239-46.
• [8] Novel SS18-NEDD4 gene fusion in a primary renal synovial sarcoma.Genes Chromosomes Cancer. 2020 Mar;59(3):203-208. doi: 10.1002/gcc.22814. Epub 2019 Oct 21.
• [9] The presence of dominant T-cell clones in peripheral blood of patients with collagen vascular disorders: a prospective study of 97 cases.Br J Dermatol. 2006 Mar;154(3):445-9. doi: 10.1111/j.1365-2133.2005.07044.x.
• [10] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [11] Genetic analysis of SS18L1 in French amyotrophic lateral sclerosis.Neurobiol Aging. 2014 May;35(5):1213.e9-1213.e12. doi: 10.1016/j.neurobiolaging.2013.11.023. Epub 2013 Dec 3.
• [12] Which patients with ES-SCLC are most likely to benefit from more aggressive radiotherapy: A secondary analysis of the Phase III CREST trial.Lung Cancer. 2017 Jun;108:150-153. doi: 10.1016/j.lungcan.2017.03.007. Epub 2017 Mar 21.
• [13] Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma.J Clin Invest. 2018 Jan 2;128(1):294-308. doi: 10.1172/JCI92513. Epub 2017 Dec 4.
• [14] Association of clonally expanded T cells with the syndrome of primary biliary cirrhosis and limited scleroderma.Hepatology. 1999 Jun;29(6):1635-42. doi: 10.1002/hep.510290637.
• [15] Case series: rheumatological manifestations attributed to exposure to Libby Asbestiform Amphiboles.J Toxicol Environ Health A. 2018;81(15):734-747. doi: 10.1080/15287394.2018.1485124. Epub 2018 Jun 21.
• [16] Prediction Models for Clinical Outcome After a Carotid Revascularization Procedure.Stroke. 2018 Aug;49(8):1880-1885. doi: 10.1161/STROKEAHA.117.020486.
• [17] Stem cell transcriptome responses and corresponding biomarkers that indicate the transition from adaptive responses to cytotoxicity. Chem Res Toxicol. 2017 Apr 17;30(4):905-922.
• [18] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [19] Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. PLoS One. 2009 Sep 23;4(9):e7155.
• [20] 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.