Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT516T6D)

• DOT Name: Sex-determining region Y protein (SRY)
• Synonyms: Testis-determining factor
• Gene Name: SRY
• Related Disease:
  46,XX sex reversal 1
  Acute myelogenous leukaemia
  Obsolete 46,XX sex reversal 1
  46,XX testicular disorder of sex development
  46,XY disorder of sex development
  Androgen insensitivity syndrome
  Azoospermia
  Campomelic dysplasia
  Childhood kidney Wilms tumor
  Colorectal carcinoma
  Cryptorchidism
  Epithelial ovarian cancer
  Fetal growth restriction
  Gonadal dysgenesis
  Hepatitis B virus infection
  Hepatocellular carcinoma
  HIV infectious disease
  Hypogonadotropic hypogonadism
  Lung cancer
  Lung carcinoma
  Mantle cell lymphoma
  Neoplasm
  Non-small-cell lung cancer
  Osteoarthritis
  Osteoporosis
  Parkinson disease
  Prostate cancer
  Prostate carcinoma
  Thyroid gland follicular carcinoma
  Wilms tumor
  46,XX disorder of sex development
  Hypogonadism, male
  Male infertility
  46,XX ovotesticular disorder of sex development
  46,XY complete gonadal dysgenesis
  46,XY partial gonadal dysgenesis
  Esophageal squamous cell carcinoma
  Breast cancer
  Breast carcinoma
  Gastric cancer
  Pancreatic cancer
  Scleroderma
  Stomach cancer
  Systemic sclerosis
• UniProt ID: SRY_HUMAN
• PDB ID: 1HRY; 1HRZ; 1J46; 1J47; 2GZK; 6EDB; 7YHO; 7YHP; 7YHQ
• Pfam ID: PF00505
• Sequence:
  MQSYASAMLSVFNSDDYSPAVQENIPALRRSSSFLCTESCNSKYQCETGENSKGNVQDRV
  KRPMNAFIVWSRDQRRKMALENPRMRNSEISKQLGYQWKMLTEAEKWPFFQEAQKLQAMH
  REKYPNYKYRPRRKAKMLPKNCSLLPADPASVLCSEVQLDNRLYRDDCTKATHSRMEHQL
  GHLPPINAASSPQQRDRYSHWTKL
• Function: Transcriptional regulator that controls a genetic switch in male development. It is necessary and sufficient for initiating male sex determination by directing the development of supporting cell precursors (pre-Sertoli cells) as Sertoli rather than granulosa cells. Involved in different aspects of gene regulation including promoter activation or repression. Binds to the DNA consensus sequence 5'-[AT]AACAA[AT]-3'. SRY HMG box recognizes DNA by partial intercalation in the minor groove and promotes DNA bending. Also involved in pre-mRNA splicing. In male adult brain involved in the maintenance of motor functions of dopaminergic neurons.
• Reactome Pathway:
  Transcriptional regulation of testis differentiation (R-HSA-9690406)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
46,XX sex reversal 1	DISRDCZR	Definitive	X-linked	[1]
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[2]
Obsolete 46,XX sex reversal 1	DIS79VJ6	Definitive	X-linked	[3]
46,XX testicular disorder of sex development	DISTZBTV	Strong	Genetic Variation	[4]
46,XY disorder of sex development	DIS78CGG	Strong	Genetic Variation	[5]
Androgen insensitivity syndrome	DISUZBBO	Strong	Genetic Variation	[6]
Azoospermia	DIS94181	Strong	Genetic Variation	[7]
Campomelic dysplasia	DISVTW53	Strong	Genetic Variation	[8]
Childhood kidney Wilms tumor	DIS0NMK3	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Cryptorchidism	DISYUD2P	Strong	Biomarker	[11]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[12]
Fetal growth restriction	DIS5WEJ5	Strong	Genetic Variation	[13]
Gonadal dysgenesis	DISIL2ZI	Strong	Genetic Variation	[14]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[15]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[16]
HIV infectious disease	DISO97HC	Strong	Biomarker	[17]
Hypogonadotropic hypogonadism	DIS8JSKR	Strong	Biomarker	[18]
Lung cancer	DISCM4YA	Strong	Altered Expression	[19]
Lung carcinoma	DISTR26C	Strong	Altered Expression	[19]
Mantle cell lymphoma	DISFREOV	Strong	Altered Expression	[20]
Neoplasm	DISZKGEW	Strong	Biomarker	[21]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[22]
Osteoarthritis	DIS05URM	Strong	Biomarker	[23]
Osteoporosis	DISF2JE0	Strong	Altered Expression	[24]
Parkinson disease	DISQVHKL	Strong	Biomarker	[25]
Prostate cancer	DISF190Y	Strong	Biomarker	[26]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[26]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Biomarker	[27]
Wilms tumor	DISB6T16	Strong	Genetic Variation	[9]
46,XX disorder of sex development	DISJOG7M	moderate	Biomarker	[28]
Hypogonadism, male	DISV1F5R	moderate	Genetic Variation	[29]
Male infertility	DISY3YZZ	moderate	Genetic Variation	[30]
46,XX ovotesticular disorder of sex development	DISQO3XF	Supportive	Autosomal dominant	[31]
46,XY complete gonadal dysgenesis	DISLF3LT	Supportive	Autosomal dominant	[32]
46,XY partial gonadal dysgenesis	DISMNH0C	Supportive	Autosomal dominant	[33]
Esophageal squamous cell carcinoma	DIS5N2GV	Disputed	Altered Expression	[34]
Breast cancer	DIS7DPX1	Limited	Biomarker	[35]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[35]
Gastric cancer	DISXGOUK	Limited	Altered Expression	[36]
Pancreatic cancer	DISJC981	Limited	Biomarker	[37]
Scleroderma	DISVQ342	Limited	Biomarker	[38]
Stomach cancer	DISKIJSX	Limited	Altered Expression	[36]
Systemic sclerosis	DISF44L6	Limited	Biomarker	[38]

5 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 Sex-determining region Y protein (SRY).	[39]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Sex-determining region Y protein (SRY).	[40]
DTI-015	DMXZRW0	Approved	DTI-015 decreases the expression of Sex-determining region Y protein (SRY).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Sex-determining region Y protein (SRY).	[42]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Sex-determining region Y protein (SRY).	[45]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Sex-determining region Y protein (SRY).	[43]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
MG-132	DMKA2YS	Preclinical	MG-132 decreases the degradation of Sex-determining region Y protein (SRY).	[44]

References

• [1] Mutational analysis of SRY: nonsense and missense mutations in XY sex reversal. Hum Genet. 1992 Feb;88(4):471-4. doi: 10.1007/BF00215684.
• [2] Prognostic significance of SOX2, SOX3, SOX11, SOX14 and SOX18 gene expression in adult de novo acute myeloid leukemia.Leuk Res. 2018 Apr;67:32-38. doi: 10.1016/j.leukres.2018.02.001. Epub 2018 Feb 6.
• [3] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [4] A Follow-Up from Infancy to Puberty in a Japanese Male with SRY-Negative 46,XX Testicular Disorder of Sex Development Carrying a p.Arg92Trp Mutation in NR5A1.Sex Dev. 2019;13(2):60-66. doi: 10.1159/000496777. Epub 2019 Feb 9.
• [5] Maternal uniparental disomy for chromosome 6 in a patient with IUGR, ambiguous genitalia, and persistent mullerian structures.Am J Med Genet A. 2016 Dec;170(12):3227-3230. doi: 10.1002/ajmg.a.37876. Epub 2016 Aug 8.
• [6] Case report of whole genome sequencing in the XY female: identification of a novel SRY mutation and revision of a misdiagnosis of androgen insensitivity syndrome.BMC Endocr Disord. 2016 Nov 8;16(1):58. doi: 10.1186/s12902-016-0141-7.
• [7] Localization of the SRY Gene on Chromosome 3 in a Patient with Azoospermia and a Complex Karyotype 45,X/46,X,i(Y)(q10)/46,XX/ 47,XX,i(Y)(q10).Cytogenet Genome Res. 2018;156(3):134-139. doi: 10.1159/000494464. Epub 2018 Nov 23.
• [8] De novo 12;17 translocation upstream of SOX9 resulting in 46,XX testicular disorder of sex development.Am J Med Genet A. 2010 Feb;152A(2):422-6. doi: 10.1002/ajmg.a.33201.
• [9] Mutations in SRY and WT1 genes required for gonadal development are not responsible for XY partial gonadal dysgenesis.Braz J Med Biol Res. 2005 Jan;38(1):17-25. doi: 10.1590/s0100-879x2005000100004. Epub 2005 Jan 18.
• [10] NEDD9 Inhibition by miR-25-5p Activation Is Critically Involved in Co-Treatment of Melatonin- and Pterostilbene-Induced Apoptosis in Colorectal Cancer Cells.Cancers (Basel). 2019 Oct 29;11(11):1684. doi: 10.3390/cancers11111684.
• [11] Polymorphisms of MAMLD1, SRD5A2, and AR Candidate Genes in Seven Dogs (78,XY; SRY-Positive) Affected by Hypospadias or Cryptorchidism.Sex Dev. 2019;13(2):92-98. doi: 10.1159/000500219. Epub 2019 May 4.
• [12] MicroRNA-223-3p Regulates Ovarian Cancer Cell Proliferation and Invasion by Targeting SOX11 Expression.Int J Mol Sci. 2017 Jun 6;18(6):1208. doi: 10.3390/ijms18061208.
• [13] Quantification of extracellular DNA using hypermethylated RASSF1A, SRY, and GLO sequences--evaluation of diagnostic possibilities for predicting placental insufficiency.DNA Cell Biol. 2010 Jun;29(6):295-301. doi: 10.1089/dna.2009.0971.
• [14] Rapid Molecular Genetic Diagnosis with Next-Generation Sequencing in 46,XY Disorders of Sex Development Cases: Efficiency and Cost Assessment.Horm Res Paediatr. 2017;87(2):81-87. doi: 10.1159/000452995. Epub 2016 Nov 30.
• [15] Brief Report: Relationship Between ABCC4 SNPs and Hepatitis B Virus Suppression During Tenofovir-Containing Antiretroviral Therapy in Patients With HIV/HBV Coinfection.J Acquir Immune Defic Syndr. 2019 Dec 1;82(4):421-425. doi: 10.1097/QAI.0000000000002136.
• [16] lncRNA MEG3 inhibits the growth of hepatocellular carcinoma cells by sponging miR-9-5p to upregulate SOX11.Braz J Med Biol Res. 2019;52(10):e8631. doi: 10.1590/1414-431X20198631. Epub 2019 Sep 16.
• [17] Urine assay for tenofovir to monitor adherence in real time to tenofovir disoproxil fumarate/emtricitabine as pre-exposure prophylaxis.HIV Med. 2017 Jul;18(6):412-418. doi: 10.1111/hiv.12518. Epub 2017 Apr 26.
• [18] SOX2 regulates the hypothalamic-pituitary axis at multiple levels.J Clin Invest. 2012 Oct;122(10):3635-46. doi: 10.1172/JCI64311. Epub 2012 Sep 4.
• [19] Microarray data re-annotation reveals specific lncRNAs and their potential functions in non-small cell lung cancer subtypes.Mol Med Rep. 2017 Oct;16(4):5129-5136. doi: 10.3892/mmr.2017.7244. Epub 2017 Aug 14.
• [20] Increased tumour angiogenesis in SOX11-positive mantle cell lymphoma.Histopathology. 2019 Nov;75(5):704-714. doi: 10.1111/his.13935. Epub 2019 Aug 19.
• [21] Novel role of sex-determining region Y-box 7 (SOX7) in tumor biology and cardiovascular developmental biology.Semin Cancer Biol. 2020 Dec;67(Pt 1):49-56. doi: 10.1016/j.semcancer.2019.08.032. Epub 2019 Aug 29.
• [22] Tumor-associated macrophages promote tumor metastasis via the TGF-/SOX9 axis in non-small cell lung cancer.Oncotarget. 2017 Sep 16;8(59):99801-99815. doi: 10.18632/oncotarget.21068. eCollection 2017 Nov 21.
• [23] Dual functional nanoparticles containing SOX duo and ANGPT4 shRNA for osteoarthritis treatment.J Biomed Mater Res B Appl Biomater. 2020 Jan;108(1):234-242. doi: 10.1002/jbm.b.34383. Epub 2019 Apr 8.
• [24] Sex-determining region Y (SRY) attributes to gender differences in RANKL expression and incidence of osteoporosis.Exp Mol Med. 2019 Aug 14;51(8):1-16. doi: 10.1038/s12276-019-0294-3.
• [25] Sex: A Significant Risk Factor for Neurodevelopmental and Neurodegenerative Disorders.Brain Sci. 2018 Aug 13;8(8):154. doi: 10.3390/brainsci8080154.
• [26] Correlation of SOX9 and NM23 genes with the incidence and prognosis of prostate cancer.Oncol Lett. 2019 Feb;17(2):2296-2302. doi: 10.3892/ol.2018.9828. Epub 2018 Dec 12.
• [27] Renal function and risk factors for renal disease for patients receiving HIV pre-exposure prophylaxis at an inner metropolitan health service.PLoS One. 2019 Jan 17;14(1):e0210106. doi: 10.1371/journal.pone.0210106. eCollection 2019.
• [28] Clinical and genetic analysis in males with 46,XX disorders of sex development: A reproductive centre experience of 144 cases.Andrologia. 2019 May;51(4):e13232. doi: 10.1111/and.13232. Epub 2019 Jan 8.
• [29] Cytogenetic and molecular characterization of the derivative Y chromosome: a case study of an azoospermic patient.Clin Genet. 2007 Nov;72(5):460-3. doi: 10.1111/j.1399-0004.2007.00885.x.
• [30] SRY and AZF gene variation in male infertility: a cytogenetic and molecular approach.Int Urol Nephrol. 2007;39(4):1183-9. doi: 10.1007/s11255-006-9116-3. Epub 2007 Aug 31.
• [31] The role of the sex-determining region of the Y chromosome (SRY) in the etiology of 46,XX true hermaphroditism. Hum Genet. 1992 Feb;88(4):411-6. doi: 10.1007/BF00215675.
• [32] Nonsyndromic Disorders of Testicular Development Overview. 2008 May 21 [updated 2022 Aug 18]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(?) [Internet]. Seattle (WA): University of Washington, Seattle; 1993C2024.
• [33] Primary amenorrhea in a 46,XY adolescent girl with partial gonadal dysgenesis: identification of a new SRY gene mutation. Fertil Steril. 2007 Nov;88(5):1437.e21-5. doi: 10.1016/j.fertnstert.2007.01.048. Epub 2007 May 10.
• [34] SOX17 overexpression sensitizes chemoradiation response in esophageal cancer by transcriptional down-regulation of DNA repair and damage response genes.J Biomed Sci. 2019 Feb 18;26(1):20. doi: 10.1186/s12929-019-0510-4.
• [35] SOX5 promotes breast cancer proliferation and invasion by transactivation of EZH2.Oncol Lett. 2019 Mar;17(3):2754-2762. doi: 10.3892/ol.2019.9914. Epub 2019 Jan 9.
• [36] Sex determining region Y-box 12 (SOX12) promotes gastric cancer metastasis by upregulating MMP7 and IGF1.Cancer Lett. 2019 Jun 28;452:103-118. doi: 10.1016/j.canlet.2019.03.035. Epub 2019 Mar 25.
• [37] Sex Determining Region Y Box 9 Induces Chemoresistance in Pancreatic Cancer Cells by Induction of Putative Cancer Stem Cell Characteristics and Its High Expression Predicts Poor Prognosis.Pancreas. 2017 Nov/Dec;46(10):1296-1304. doi: 10.1097/MPA.0000000000000945.
• [38] 46, XX SRY-positive male syndrome presenting with primary hypogonadism in the setting of scleroderma.Endocr Pract. 2011 Jan-Feb;17(1):95-8. doi: 10.4158/EP10184.CR.
• [39] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [40] Gene expression in endometrial cancer cells (Ishikawa) after short time high dose exposure to progesterone. Steroids. 2008 Jan;73(1):116-28.
• [41] Gene expression profile induced by BCNU in human glioma cell lines with differential MGMT expression. J Neurooncol. 2005 Jul;73(3):189-98.
• [42] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [43] 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.
• [44] Human Sex Determination at the Edge of Ambiguity: INHERITED XY SEX REVERSAL DUE TO ENHANCED UBIQUITINATION AND PROTEASOMAL DEGRADATION OF A MASTER TRANSCRIPTION FACTOR. J Biol Chem. 2016 Oct 14;291(42):22173-22195. doi: 10.1074/jbc.M116.741959. Epub 2016 Aug 30.
• [45] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.