Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT47LWI9)

• DOT Name: Tuberin (TSC2)
• Synonyms: Tuberous sclerosis 2 protein
• Gene Name: TSC2
• Related Disease:
  Clear cell renal carcinoma
  Epilepsy
  Kidney cancer
  Kidney neoplasm
  Lung lymphangioleiomyomatosis
  Renal cell carcinoma
  Tuberculosis
  Tuberous sclerosis
  Tuberous sclerosis 1
  Tuberous sclerosis 2
  Advanced cancer
  Autism spectrum disorder
  Benign neoplasm
  Carcinoma
  Chordoma
  Cystic kidney disease
  Hamartoma
  Hereditary neoplastic syndrome
  Hydrocephalus
  Intellectual disability
  Lymphangioleiomyomatosis
  Neoplasm with perivascular epithelioid cell differentiation
  Pancreatic tumour
  Polycystic kidney disease
  Precancerous condition
  Spasm
  Thyroid gland carcinoma
  Uterine fibroids
  Leiomyoma
  Neurodegenerative disease
  Renal carcinoma
  Obsolete tuberous sclerosis complex
  Acute monocytic leukemia
  Adult hepatocellular carcinoma
  Astrocytoma
  Autism
  Brain disease
  Ependymoma
  Head-neck squamous cell carcinoma
  Squamous cell carcinoma
  West syndrome
• UniProt ID: TSC2_HUMAN
• PDB ID: 7DL2
• Pfam ID: PF11864 ; PF02145 ; PF03542
• Sequence:
  MAKPTSKDSGLKEKFKILLGLGTPRPNPRSAEGKQTEFIITAEILRELSMECGLNNRIRM
  IGQICEVAKTKKFEEHAVEALWKAVADLLQPERPLEARHAVLALLKAIVQGQGERLGVLR
  ALFFKVIKDYPSNEDLHERLEVFKALTDNGRHITYLEEELADFVLQWMDVGLSSEFLLVL
  VNLVKFNSCYLDEYIARMVQMICLLCVRTASSVDIEVSLQVLDAVVCYNCLPAESLPLFI
  VTLCRTINVKELCEPCWKLMRNLLGTHLGHSAIYNMCHLMEDRAYMEDAPLLRGAVFFVG
  MALWGAHRLYSLRNSPTSVLPSFYQAMACPNEVVSYEIVLSITRLIKKYRKELQVVAWDI
  LLNIIERLLQQLQTLDSPELRTIVHDLLTTVEELCDQNEFHGSQERYFELVERCADQRPE
  SSLLNLISYRAQSIHPAKDGWIQNLQALMERFFRSESRGAVRIKVLDVLSFVLLINRQFY
  EEELINSVVISQLSHIPEDKDHQVRKLATQLLVDLAEGCHTHHFNSLLDIIEKVMARSLS
  PPPELEERDVAAYSASLEDVKTAVLGLLVILQTKLYTLPASHATRVYEMLVSHIQLHYKH
  SYTLPIASSIRLQAFDFLLLLRADSLHRLGLPNKDGVVRFSPYCVCDYMEPERGSEKKTS
  GPLSPPTGPPGPAPAGPAVRLGSVPYSLLFRVLLQCLKQESDWKVLKLVLGRLPESLRYK
  VLIFTSPCSVDQLCSALCSMLSGPKTLERLRGAPEGFSRTDLHLAVVPVLTALISYHNYL
  DKTKQREMVYCLEQGLIHRCASQCVVALSICSVEMPDIIIKALPVLVVKLTHISATASMA
  VPLLEFLSTLARLPHLYRNFAAEQYASVFAISLPYTNPSKFNQYIVCLAHHVIAMWFIRC
  RLPFRKDFVPFITKGLRSNVLLSFDDTPEKDSFRARSTSLNERPKSLRIARPPKQGLNNS
  PPVKEFKESSAAEAFRCRSISVSEHVVRSRIQTSLTSASLGSADENSVAQADDSLKNLHL
  ELTETCLDMMARYVFSNFTAVPKRSPVGEFLLAGGRTKTWLVGNKLVTVTTSVGTGTRSL
  LGLDSGELQSGPESSSSPGVHVRQTKEAPAKLESQAGQQVSRGARDRVRSMSGGHGLRVG
  ALDVPASQFLGSATSPGPRTAPAAKPEKASAGTRVPVQEKTNLAAYVPLLTQGWAEILVR
  RPTGNTSWLMSLENPLSPFSSDINNMPLQELSNALMAAERFKEHRDTALYKSLSVPAAST
  AKPPPLPRSNTVASFSSLYQSSCQGQLHRSVSWADSAVVMEEGSPGEVPVLVEPPGLEDV
  EAALGMDRRTDAYSRSSSVSSQEEKSLHAEELVGRGIPIERVVSSEGGRPSVDLSFQPSQ
  PLSKSSSSPELQTLQDILGDPGDKADVGRLSPEVKARSQSGTLDGESAAWSASGEDSRGQ
  PEGPLPSSSPRSPSGLRPRGYTISDSAPSRRGKRVERDALKSRATASNAEKVPGINPSFV
  FLQLYHSPFFGDESNKPILLPNESQSFERSVQLLDQIPSYDTHKIAVLYVGEGQSNSELA
  ILSNEHGSYRYTEFLTGLGRLIELKDCQPDKVYLGGLDVCGEDGQFTYCWHDDIMQAVFH
  IATLMPTKDVDKHRCDKKRHLGNDFVSIVYNDSGEDFKLGTIKGQFNFVHVIVTPLDYEC
  NLVSLQCRKDMEGLVDTSVAKIVSDRNLPFVARQMALHANMASQVHHSRSNPTDIYPSKW
  IARLRHIKRLRQRICEEAAYSNPSLPLVHPPSHSKAPAQTPAEPTPGYEVGQRKRLISSV
  EDFTEFV
• Function: Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation and growth. Within the TSC-TBC complex, TSC2 acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1. In absence of nutrients, the TSC-TBC complex inhibits mTORC1, thereby preventing phosphorylation of ribosomal protein S6 kinase (RPS6KB1 and RPS6KB2) and EIF4EBP1 (4E-BP1) by the mTORC1 signaling. The TSC-TBC complex is inactivated in response to nutrients, relieving inhibition of mTORC1. Involved in microtubule-mediated protein transport via its ability to regulate mTORC1 signaling. Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5.
• Tissue Specificity: Liver, brain, heart, lymphocytes, fibroblasts, biliary epithelium, pancreas, skeletal muscle, kidney, lung and placenta.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  p53 sig.ling pathway (hsa04115)
  Autophagy - animal (hsa04140)
  mTOR sig.ling pathway (hsa04150)
  PI3K-Akt sig.ling pathway (hsa04151)
  AMPK sig.ling pathway (hsa04152)
  Longevity regulating pathway (hsa04211)
  Cellular senescence (hsa04218)
  Thermogenesis (hsa04714)
  Insulin sig.ling pathway (hsa04910)
  Thyroid hormone sig.ling pathway (hsa04919)
  Human cytomegalovirus infection (hsa05163)
  Human papillomavirus infection (hsa05165)
  Herpes simplex virus 1 infection (hsa05168)
  Choline metabolism in cancer (hsa05231)
• Reactome Pathway:
  Inhibition of TSC complex formation by PKB (R-HSA-165181)
  AKT phosphorylates targets in the cytosol (R-HSA-198323)
  Energy dependent regulation of mTOR by LKB1-AMPK (R-HSA-380972)
  TP53 Regulates Metabolic Genes (R-HSA-5628897)
  Constitutive Signaling by AKT1 E17K in Cancer (R-HSA-5674400)
  TBC/RABGAPs (R-HSA-8854214)
  Macroautophagy (R-HSA-1632852)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Clear cell renal carcinoma	DISBXRFJ	Definitive	Genetic Variation	[1]
Epilepsy	DISBB28L	Definitive	Biomarker	[2]
Kidney cancer	DISBIPKM	Definitive	Biomarker	[3]
Kidney neoplasm	DISBNZTN	Definitive	Biomarker	[4]
Lung lymphangioleiomyomatosis	DISFL3YB	Definitive	Autosomal dominant	[5]
Renal cell carcinoma	DISQZ2X8	Definitive	Genetic Variation	[1]
Tuberculosis	DIS2YIMD	Definitive	Biomarker	[6]
Tuberous sclerosis	DISEMUGZ	Definitive	Autosomal dominant	[7]
Tuberous sclerosis 1	DIS07GDN	Definitive	Biomarker	[8]
Tuberous sclerosis 2	DISR6GKZ	Definitive	Autosomal dominant	[9]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[10]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[11]
Benign neoplasm	DISDUXAD	Strong	Genetic Variation	[12]
Carcinoma	DISH9F1N	Strong	Biomarker	[13]
Chordoma	DISCHJE7	Strong	Genetic Variation	[14]
Cystic kidney disease	DISRT1LM	Strong	Altered Expression	[15]
Hamartoma	DIS0I87H	Strong	Genetic Variation	[16]
Hereditary neoplastic syndrome	DISGXLG5	Strong	CausalMutation	[17]
Hydrocephalus	DISIZUF7	Strong	Biomarker	[18]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[19]
Lymphangioleiomyomatosis	DISR0RNB	Strong	Autosomal dominant	[9]
Neoplasm with perivascular epithelioid cell differentiation	DIS8V0NT	Strong	Genetic Variation	[12]
Pancreatic tumour	DIS3U0LK	Strong	Biomarker	[20]
Polycystic kidney disease	DISWS3UY	Strong	Genetic Variation	[21]
Precancerous condition	DISV06FL	Strong	Biomarker	[22]
Spasm	DIS51WT2	Strong	Biomarker	[23]
Thyroid gland carcinoma	DISMNGZ0	Strong	Biomarker	[24]
Uterine fibroids	DISBZRMJ	Strong	Biomarker	[25]
Leiomyoma	DISLDDFN	moderate	Altered Expression	[26]
Neurodegenerative disease	DISM20FF	moderate	Biomarker	[27]
Renal carcinoma	DISER9XT	moderate	Biomarker	[3]
Obsolete tuberous sclerosis complex	DIS46L2J	Supportive	Autosomal dominant	[28]
Acute monocytic leukemia	DIS28NEL	Limited	Genetic Variation	[29]
Adult hepatocellular carcinoma	DIS6ZPAI	Limited	Genetic Variation	[30]
Astrocytoma	DISL3V18	Limited	Genetic Variation	[31]
Autism	DISV4V1Z	Limited	Biomarker	[32]
Brain disease	DIS6ZC3X	Limited	Biomarker	[33]
Ependymoma	DISUMRNZ	Limited	Biomarker	[34]
Head-neck squamous cell carcinoma	DISF7P24	Limited	Altered Expression	[35]
Squamous cell carcinoma	DISQVIFL	Limited	Biomarker	[36]
West syndrome	DISLIAU9	Limited	Genetic Variation	[37]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tuberin (TSC2).	[38]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Tuberin (TSC2).	[43]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the phosphorylation of Tuberin (TSC2).	[49]
Methamphetamine	DMPM4SK	Approved	Methamphetamine increases the phosphorylation of Tuberin (TSC2).	[51]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the phosphorylation of Tuberin (TSC2).	[54]
GDC-0980/RG7422	DMF3MV1	Phase 2	GDC-0980/RG7422 decreases the phosphorylation of Tuberin (TSC2).	[55]
GSK690693	DMRBVHE	Phase 1	GSK690693 decreases the phosphorylation of Tuberin (TSC2).	[55]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Tuberin (TSC2).	[56]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Tuberin (TSC2).	[39]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Tuberin (TSC2).	[40]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Tuberin (TSC2).	[41]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Tuberin (TSC2).	[42]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Tuberin (TSC2).	[44]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Tuberin (TSC2).	[45]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Tuberin (TSC2).	[46]
Selenium	DM25CGV	Approved	Selenium increases the expression of Tuberin (TSC2).	[47]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Tuberin (TSC2).	[48]
Azacitidine	DMTA5OE	Approved	Azacitidine increases the expression of Tuberin (TSC2).	[50]
Sodium phenylbutyrate	DMXLBCQ	Approved	Sodium phenylbutyrate increases the expression of Tuberin (TSC2).	[52]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Tuberin (TSC2).	[53]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Tuberin (TSC2).	[47]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tuberin (TSC2).	[57]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Tuberin (TSC2).	[58]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Tuberin (TSC2).	[45]

References

• [1] PTEN expression and mutations in TSC1, TSC2 and MTOR are associated with response to rapalogs in patients with renal cell carcinoma.Int J Cancer. 2020 Mar 1;146(5):1435-1444. doi: 10.1002/ijc.32579. Epub 2019 Aug 9.
• [2] LAM study: Effects of lacosamide on behaviour and quality of life in patients with epilepsy.Neurologia (Engl Ed). 2019 Jan-Feb;34(1):1-6. doi: 10.1016/j.nrl.2016.10.007. Epub 2016 Dec 16.
• [3] Heterozygous Tsc2 (Tsc2+/-) mouse model to study induced renal cancer in response to ionizing radiation at low doses.Carcinogenesis. 2019 Jul 6;40(6):782-790. doi: 10.1093/carcin/bgy172.
• [4] mTOR-dependent upregulation of xCT blocks melanin synthesis and promotes tumorigenesis.Cell Death Differ. 2019 Oct;26(10):2015-2028. doi: 10.1038/s41418-019-0274-0. Epub 2019 Feb 13.
• [5] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [6] Lateral Flow Urine Lipoarabinomannan Assay for Diagnosis of Active Tuberculosis in Adults With Human Immunodeficiency Virus Infection: A Prospective Cohort Study.Open Forum Infect Dis. 2019 Mar 15;6(4):ofz132. doi: 10.1093/ofid/ofz132. eCollection 2019 Apr.
• [7] 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.
• [8] Striatal Transcriptome and Interactome Analysis of Shank3-overexpressing Mice Reveals the Connectivity between Shank3 and mTORC1 Signaling.Front Mol Neurosci. 2017 Jun 28;10:201. doi: 10.3389/fnmol.2017.00201. eCollection 2017.
• [9] 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.
• [10] Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells.Invest New Drugs. 2020 Jun;38(3):558-573. doi: 10.1007/s10637-019-00789-1. Epub 2019 Jun 8.
• [11] Targeted resequencing of 358 candidate genes for autism spectrum disorder in a Chinese cohort reveals diagnostic potential and genotype-phenotype correlations. Hum Mutat. 2019 Jun;40(6):801-815. doi: 10.1002/humu.23724. Epub 2019 Apr 29.
• [12] Benign clear cell "sugar" tumor of the lung in a patient with Birt-Hogg-Dub syndrome: a case report.BMC Med Genet. 2016 Nov 21;17(1):85. doi: 10.1186/s12881-016-0350-y.
• [13] Loss of heterozygosity is detected at chromosomes 1p35-36 (NB), 3p25 (VHL), 16p13 (TSC2/PKD1), and 17p13 (TP53) in microdissected apocrine carcinomas of the breast.Mod Pathol. 1999 Dec;12(12):1083-9.
• [14] Clinical features distinguish childhood chordoma associated with tuberous sclerosis complex (TSC) from chordoma in the general paediatric population.J Med Genet. 2011 Jul;48(7):444-9. doi: 10.1136/jmg.2010.085092. Epub 2011 Jan 25.
• [15] Inactivation of Tsc2 in Mesoderm-Derived Cells Causes Polycystic Kidney Lesions and Impairs Lung Alveolarization.Am J Pathol. 2016 Dec;186(12):3261-3272. doi: 10.1016/j.ajpath.2016.08.013. Epub 2016 Oct 18.
• [16] Decoding of novel missense TSC2 gene variants using in-silico methods.BMC Med Genet. 2019 Oct 26;20(1):164. doi: 10.1186/s12881-019-0891-y.
• [17] TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex.Am J Med Genet A. 2017 Mar;173(3):771-775. doi: 10.1002/ajmg.a.38083.
• [18] Initial experience with endoscopic ultrasonic aspirator in purely neuroendoscopic removal of intraventricular tumors.J Neurosurg Pediatr. 2017 Mar;19(3):325-332. doi: 10.3171/2016.10.PEDS16352. Epub 2017 Jan 13.
• [19] Tuberous Sclerosis Complex Genotypes and Developmental Phenotype.Pediatr Neurol. 2019 Jul;96:58-63. doi: 10.1016/j.pediatrneurol.2019.03.003. Epub 2019 Mar 13.
• [20] Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway.J Clin Oncol. 2010 Jan 10;28(2):245-55. doi: 10.1200/JCO.2008.21.5988. Epub 2009 Nov 16.
• [21] TSC2/PKD1 contiguous gene syndrome, with emphasis on a case with an atypical mild polycystic kidney phenotype and a novel genetic variant.Nefrologia (Engl Ed). 2020 Jan-Feb;40(1):91-98. doi: 10.1016/j.nefro.2019.03.003. Epub 2019 Jun 5.
• [22] Predominant Activation of JAK/STAT3 Pathway by Interleukin-6 Is Implicated in Hepatocarcinogenesis.Neoplasia. 2015 Jul;17(7):586-97. doi: 10.1016/j.neo.2015.07.005.
• [23] Management of epilepsy in tuberous sclerosis complex.Expert Rev Neurother. 2008 Mar;8(3):457-67. doi: 10.1586/14737175.8.3.457.
• [24] Papillary thyroid carcinoma in a boy with familial tuberous sclerosis complex attributable to a TSC2 deletion-a case report.Curr Oncol. 2017 Oct;24(5):e423-e428. doi: 10.3747/co.24.3555. Epub 2017 Oct 25.
• [25] Deficient TSC1/TSC2-complex suppression of SOX9-osteopontin-AKT signalling cascade constrains tumour growth in tuberous sclerosis complex.Hum Mol Genet. 2017 Jan 15;26(2):407-419. doi: 10.1093/hmg/ddw397.
• [26] Increased expression of tuberin in human uterine leiomyoma.Fertil Steril. 2011 Apr;95(5):1805-8. doi: 10.1016/j.fertnstert.2010.11.028. Epub 2010 Dec 10.
• [27] Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration.Neurobiol Dis. 2011 Jul;43(1):113-22. doi: 10.1016/j.nbd.2011.02.014. Epub 2011 Mar 17.
• [28] Tuberous Sclerosis Complex. 1999 Jul 13 [updated 2021 Dec 9]. 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.
• [29] Two novel TSC2 mutations in renal epithelioid angiomyolipoma sensitive to everolimus.Cancer Biol Ther. 2020;21(1):4-11. doi: 10.1080/15384047.2019.1665955. Epub 2019 Oct 10.
• [30] TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.Gut. 2017 Aug;66(8):1496-1506. doi: 10.1136/gutjnl-2016-312734. Epub 2016 Dec 14.
• [31] Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2.Eur J Med Genet. 2018 Jul;61(7):403-410. doi: 10.1016/j.ejmg.2018.02.005. Epub 2018 Feb 9.
• [32] mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.Eur Arch Psychiatry Clin Neurosci. 2017 Aug;267(5):455-463. doi: 10.1007/s00406-016-0703-8. Epub 2016 Jun 4.
• [33] Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex.Hum Mol Genet. 2011 Feb 1;20(3):445-54. doi: 10.1093/hmg/ddq491. Epub 2010 Nov 9.
• [34] Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas.Ann Neurol. 1997 Aug;42(2):230-5. doi: 10.1002/ana.410420215.
• [35] ERK-TSC2 signalling in constitutively-active HRAS mutant HNSCC cells promotes resistance to PI3K inhibition.Oral Oncol. 2018 Sep;84:95-103. doi: 10.1016/j.oraloncology.2018.07.010. Epub 2018 Jul 27.
• [36] Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma.BMC Cancer. 2008 Jun 6;8:163. doi: 10.1186/1471-2407-8-163.
• [37] Severity of manifestations in tuberous sclerosis complex in relation to genotype.Epilepsia. 2014 Jul;55(7):1025-9. doi: 10.1111/epi.12680. Epub 2014 Jun 10.
• [38] 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.
• [39] 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.
• [40] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [41] Mechanism of cisplatin proximal tubule toxicity revealed by integrating transcriptomics, proteomics, metabolomics and biokinetics. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):117-27.
• [42] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [43] 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.
• [44] Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol. 2004 Jan;11(1):63-9. doi: 10.1128/cdli.11.1.63-69.2004.
• [45] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [46] The contribution of methotrexate exposure and host factors on transcriptional variance in human liver. Toxicol Sci. 2007 Jun;97(2):582-94.
• [47] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [48] 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.
• [49] Rosiglitazone, an Agonist of PPARgamma, Inhibits Non-Small Cell Carcinoma Cell Proliferation In Part through Activation of Tumor Sclerosis Complex-2. PPAR Res. 2007;2007:29632. doi: 10.1155/2007/29632.
• [50] Aberrant expression of TSC2 gene in the newly diagnosed acute leukemia. Leuk Res. 2009 Jul;33(7):891-7. doi: 10.1016/j.leukres.2009.01.041. Epub 2009 Feb 27.
• [51] Involvement of C/EBP-related signaling pathway in methamphetamine-induced neuronal autophagy and apoptosis. Toxicol Lett. 2019 Sep 15;312:11-21. doi: 10.1016/j.toxlet.2019.05.003. Epub 2019 May 3.
• [52] Gene expression profile analysis of 4-phenylbutyrate treatment of IB3-1 bronchial epithelial cell line demonstrates a major influence on heat-shock proteins. Physiol Genomics. 2004 Jan 15;16(2):204-11.
• [53] Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis. FASEB J. 2013 Apr;27(4):1561-71. doi: 10.1096/fj.12-220129. Epub 2013 Jan 4.
• [54] Curcumin inhibits Akt/mammalian target of rapamycin signaling through protein phosphatase-dependent mechanism. Mol Cancer Ther. 2008 Sep;7(9):2609-20. doi: 10.1158/1535-7163.MCT-07-2400.
• [55] Modulation of Akt/mTOR signaling overcomes sunitinib resistance in renal and prostate cancer cells. Mol Cancer Ther. 2012 Jul;11(7):1510-7. doi: 10.1158/1535-7163.MCT-11-0907. Epub 2012 Apr 24.
• [56] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [57] Activation of the mTOR pathway by low levels of xenoestrogens in breast epithelial cells from high-risk women. Carcinogenesis. 2011 Nov;32(11):1724-33. doi: 10.1093/carcin/bgr196. Epub 2011 Sep 1.
• [58] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.