Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYKC1AJ)

• DOT Name: Speedy protein A (SPDYA)
• Synonyms: Rapid inducer of G2/M progression in oocytes A; RINGO A; hSpy/Ringo A; Speedy-1; Spy1
• Gene Name: SPDYA
• Related Disease:
  Breast cancer
  Breast carcinoma
  Advanced cancer
  Colorectal carcinoma
  Epithelial ovarian cancer
  Glioma
  Ovarian cancer
  Ovarian neoplasm
  Plasma cell myeloma
  Triple negative breast cancer
  Hepatocellular carcinoma
  Pneumococcal infection
  Amyotrophic lateral sclerosis
  Cutaneous mastocytosis
  Neoplasm
• UniProt ID: SPDYA_HUMAN
• PDB ID: 5UQ1; 5UQ2; 5UQ3; 7E34
• Pfam ID: PF11357
• Sequence:
  MRHNQMCCETPPTVTVYVKSGSNRSHQPKKPITLKRPICKDNWQAFEKNTHNNNKSKRPK
  GPCLVIQRQDMTAFFKLFDDDLIQDFLWMDCCCKIADKYLLAMTFVYFKRAKFTISEHTR
  INFFIALYLANTVEEDEEETKYEIFPWALGKNWRKLFPNFLKLRDQLWDRIDYRAIVSRR
  CCEEVMAIAPTHYIWQRERSVHHSGAVRNYNRDEVQLPRGPSATPVDCSLCGKKRRYVRL
  GLSSSSSLSSHTAGVTEKHSQDSYNSLSMDIIGDPSQAYTGSEVVNDHQSNKGKKTNFLK
  KDKSMEWFTGSEE
• Function: Regulates the G1/S phase transition of the cell cycle by binding and activating CDK1 and CDK2. Contributes to CDK2 activation without promoting CDK2 phosphorylation, by inducing a conformation change of the CDK2 T-loop that obstructs the substrate-binding cleft prior to kinase activation. Mediates cell survival during the DNA damage process through activation of CDK2.
• Tissue Specificity: Highly expressed in testis. Expressed at a low level in wide range of tissues including bone marrow, brain, heart, kidney, colon, liver, placenta, spleen, skeletal muscle, salivary gland, thyroid gland, thymus, trachea and uterus. Expressed at a slightly higher level in adrenal gland, cerebellum, small intestine, lung, prostate and trachea. Expression is cell cycle-dependent, being restricted to cells in G1/S phase.
• KEGG Pathway:
  Oocyte meiosis (hsa04114)
  Progesterone-mediated oocyte maturation (hsa04914)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Definitive	Altered Expression	[1]
Breast carcinoma	DIS2UE88	Definitive	Altered Expression	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[4]
Glioma	DIS5RPEH	Strong	Biomarker	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[4]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[4]
Plasma cell myeloma	DIS0DFZ0	Strong	Biomarker	[6]
Triple negative breast cancer	DISAMG6N	Strong	Genetic Variation	[7]
Hepatocellular carcinoma	DIS0J828	moderate	Altered Expression	[8]
Pneumococcal infection	DIS6SXQD	moderate	Biomarker	[9]
Amyotrophic lateral sclerosis	DISF7HVM	Disputed	Biomarker	[10]
Cutaneous mastocytosis	DISLBZEF	Limited	Biomarker	[11]
Neoplasm	DISZKGEW	Limited	Biomarker	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Speedy protein A (SPDYA).	[12]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Speedy protein A (SPDYA).	[13]
Dihydrotestosterone	DM3S8XC	Phase 4	Dihydrotestosterone increases the expression of Speedy protein A (SPDYA).	[14]

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 affects the methylation of Speedy protein A (SPDYA).	[15]

References

• [1] Epigenetic inhibition of the tumor suppressor ARHI by light at night-induced circadian melatonin disruption mediates STAT3-driven paclitaxel resistance in breast cancer.J Pineal Res. 2019 Sep;67(2):e12586. doi: 10.1111/jpi.12586. Epub 2019 Jun 9.
• [2] Structural basis of divergent cyclin-dependent kinase activation by Spy1/RINGO proteins.EMBO J. 2017 Aug 1;36(15):2251-2262. doi: 10.15252/embj.201796905. Epub 2017 Jun 30.
• [3] High Spy1 expression predicts poor prognosis in colorectal cancer.Cancer Manag Res. 2018 Aug 16;10:2757-2765. doi: 10.2147/CMAR.S169329. eCollection 2018.
• [4] Spy1 participates in the proliferation and apoptosis of epithelial ovarian cancer.J Mol Histol. 2016 Feb;47(1):47-57. doi: 10.1007/s10735-015-9646-z. Epub 2015 Dec 7.
• [5] The cyclin-like protein Spy1 regulates growth and division characteristics of the CD133+ population in human glioma.Cancer Cell. 2014 Jan 13;25(1):64-76. doi: 10.1016/j.ccr.2013.12.006.
• [6] Cell adhesion to fibronectin down-regulates the expression of Spy1 and contributes to drug resistance in multiple myeloma cells.Int J Hematol. 2013 Oct;98(4):446-55. doi: 10.1007/s12185-013-1435-4. Epub 2013 Sep 14.
• [7] Magnetic resonance imaging and molecular features associated with tumor-infiltrating lymphocytes in breast cancer.Breast Cancer Res. 2018 Sep 3;20(1):101. doi: 10.1186/s13058-018-1039-2.
• [8] Cyclin-like proteins tip regenerative balance in the liver to favour cancer formation.Carcinogenesis. 2020 Jul 10;41(6):850-862. doi: 10.1093/carcin/bgz164.
• [9] Protective Regulatory T Cell Immune Response Induced by Intranasal Immunization With the Live-Attenuated Pneumococcal Vaccine SPY1 via the Transforming Growth Factor-1-Smad2/3 Pathway.Front Immunol. 2018 Aug 2;9:1754. doi: 10.3389/fimmu.2018.01754. eCollection 2018.
• [10] Spy1, a unique cell cycle regulator, alters viability in ALS motor neurons and cell lines in response to mutant SOD1-induced DNA damage.DNA Repair (Amst). 2019 Feb;74:51-62. doi: 10.1016/j.dnarep.2018.12.005. Epub 2018 Dec 21.
• [11] Chemotherapy response and recurrence-free survival in neoadjuvant breast cancer depends on biomarker profiles: results from the I-SPY 1 TRIAL (CALGB 150007/150012; ACRIN 6657).Breast Cancer Res Treat. 2012 Apr;132(3):1049-62. doi: 10.1007/s10549-011-1895-2. Epub 2011 Dec 25.
• [12] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [13] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [14] LSD1 activates a lethal prostate cancer gene network independently of its demethylase function. Proc Natl Acad Sci U S A. 2018 May 1;115(18):E4179-E4188.
• [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.