Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAHUNN7)

• DOT Name: RasGAP-activating-like protein 1 (RASAL1)
• Synonyms: RAS protein activator like 1; Ras GTPase-activating-like protein
• Gene Name: RASAL1
• Related Disease:
  Advanced cancer
  Adenoma
  Breast carcinoma
  Carcinoma of liver and intrahepatic biliary tract
  Colon cancer
  Colon carcinoma
  Hepatocellular carcinoma
  Liver cancer
  Meningioma
  Nephropathy
  Pulmonary fibrosis
  Thyroid gland follicular carcinoma
  Thyroid gland papillary carcinoma
  Thyroid gland undifferentiated (anaplastic) carcinoma
  Thyroid cancer
  Thyroid gland carcinoma
  Thyroid tumor
  Adenocarcinoma
  Bone osteosarcoma
  Breast cancer
  Chronic kidney disease
  Colorectal carcinoma
  Colorectal neoplasm
  Cowden disease
  Osteosarcoma
• UniProt ID: RASL1_HUMAN
• Pfam ID: PF00779 ; PF00168 ; PF00169 ; PF00616
• Sequence:
  MAKSSSLNVRVVEGRALPAKDVSGSSDPYCLVKVDDEVVARTATVWRSLGPFWGEEYTVH
  LPLDFHQLAFYVLDEDTVGHDDIIGKISLSREAITADPRGIDSWINLSRVDPDAEVQGEI
  CLSVQMLEDGQGRCLRCHVLQARDLAPRDISGTSDPFARVFWGSQSLETSTIKKTRFPHW
  DEVLELREMPGAPSPLRVELWDWDMVGKNDFLGMVEFSPKTLQQKPPKGWFRLLPFPRAE
  EDSGGNLGALRVKVRLIEDRVLPSQCYQPLMELLMESVQGPAEEDTASPLALLEELTLGD
  CRQDLATKLVKLFLGRGLAGRFLDYLTRREVARTMDPNTLFRSNSLASKSMEQFMKLVGM
  PYLHEVLKPVISRVFEEKKYMELDPCKMDLGRTRRISFKGALSEEQMRETSLGLLTGYLG
  PIVDAIVGSVGRCPPAMRLAFKQLHRRVEERFPQAEHQDVKYLAISGFLFLRFFAPAILT
  PKLFDLRDQHADPQTSRSLLLLAKAVQSIGNLGQQLGQGKELWMAPLHPFLLQCVSRVRD
  FLDRLVDVDGDEAGVPARALFPPSAIVREGYLLKRKEEPAGLATRFAFKKRYVWLSGETL
  SFSKSPEWQMCHSIPVSHIRAVERVDEGAFQLPHVMQVVTQDGTGALHTTYLQCKNVNEL
  NQWLSALRKASAPNPNKLAACHPGAFRSARWTCCLQAERSAAGCSRTHSAVTLGDWSDPL
  DPDAEAQTVYRQLLLGRDQLRLKLLEDSNMDTTLEADTGACPEVLARQRAATARLLEVLA
  DLDRAHEEFQQQERGKAALGPLGP
• Function: Probable inhibitory regulator of the Ras-cyclic AMP pathway. Plays a role in dendrite formation by melanocytes.
• Tissue Specificity: Highly expressed in thyroid and adrenal medulla, lower expression in brain, spinal cord and trachea . Expressed in melanocytes .
• KEGG Pathway: Ras sig.ling pathway (hsa04014)
• Reactome Pathway: Regulation of RAS by GAPs (R-HSA-5658442)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Strong	Biomarker	[4]
Colon cancer	DISVC52G	Strong	Biomarker	[5]
Colon carcinoma	DISJYKUO	Strong	Biomarker	[5]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[4]
Liver cancer	DISDE4BI	Strong	Biomarker	[4]
Meningioma	DISPT4TG	Strong	Genetic Variation	[6]
Nephropathy	DISXWP4P	Strong	Biomarker	[7]
Pulmonary fibrosis	DISQKVLA	Strong	Biomarker	[8]
Thyroid gland follicular carcinoma	DISFK2QT	Strong	Genetic Variation	[9]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Genetic Variation	[9]
Thyroid gland undifferentiated (anaplastic) carcinoma	DISYBB1W	Strong	Genetic Variation	[10]
Thyroid cancer	DIS3VLDH	Disputed	Biomarker	[11]
Thyroid gland carcinoma	DISMNGZ0	Disputed	Biomarker	[11]
Thyroid tumor	DISLVKMD	Disputed	Altered Expression	[11]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[12]
Bone osteosarcoma	DIST1004	Limited	Biomarker	[13]
Breast cancer	DIS7DPX1	Limited	Autosomal dominant	[14]
Chronic kidney disease	DISW82R7	Limited	Biomarker	[15]
Colorectal carcinoma	DIS5PYL0	Limited	Altered Expression	[12]
Colorectal neoplasm	DISR1UCN	Limited	Altered Expression	[12]
Cowden disease	DISMYKCE	Limited	Genetic Variation	[9]
Osteosarcoma	DISLQ7E2	Limited	Biomarker	[13]

3 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 RasGAP-activating-like protein 1 (RASAL1).	[16]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of RasGAP-activating-like protein 1 (RASAL1).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of RasGAP-activating-like protein 1 (RASAL1).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of RasGAP-activating-like protein 1 (RASAL1).	[17]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of RasGAP-activating-like protein 1 (RASAL1).	[18]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of RasGAP-activating-like protein 1 (RASAL1).	[20]
Zoledronate	DMIXC7G	Approved	Zoledronate decreases the expression of RasGAP-activating-like protein 1 (RASAL1).	[21]
Isotretinoin	DM4QTBN	Approved	Isotretinoin decreases the expression of RasGAP-activating-like protein 1 (RASAL1).	[22]
Diethylstilbestrol	DMN3UXQ	Approved	Diethylstilbestrol decreases the expression of RasGAP-activating-like protein 1 (RASAL1).	[23]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of RasGAP-activating-like protein 1 (RASAL1).	[25]

References

• [1] RASAL1 inhibits HepG2 cell growth via HIF-2 mediated gluconeogenesis.Oncol Lett. 2017 Dec;14(6):7344-7352. doi: 10.3892/ol.2017.7123. Epub 2017 Oct 3.
• [2] Reduced expression of RAS protein activator like-1 in gastric cancer.Int J Cancer. 2011 Mar 15;128(6):1293-302. doi: 10.1002/ijc.25459.
• [3] RAS protein activator-like 1 is functionally involved in hypoxia resistance in breast cancer cells by targeting hypoxia inducible factor-1.Oncol Lett. 2017 Sep;14(3):3839-3845. doi: 10.3892/ol.2017.6648. Epub 2017 Jul 21.
• [4] Long non-coding RNA TUC338 is functionally involved in sorafenib-sensitized hepatocarcinoma cells by targeting RASAL1.Oncol Rep. 2017 Jan;37(1):273-280. doi: 10.3892/or.2016.5248. Epub 2016 Nov 15.
• [5] RASAL1 induces to downregulate the SCD1, leading to suppression of cell proliferation in colon cancer via LXR/SREBP1c pathway.Biol Res. 2019 Dec 17;52(1):60. doi: 10.1186/s40659-019-0268-x.
• [6] Medullary thyroid cancer, leukemia, mesothelioma and meningioma associated with germline APC and RASAL1 variants: a new syndrome?.Hormones (Athens). 2017 Oct;16(4):423-428. doi: 10.14310/horm.2002.1763.
• [7] Hypermethylations of RASAL1 and KLOTHO is associated with renal dysfunction in a Chinese population environmentally exposed to cadmium.Toxicol Appl Pharmacol. 2013 Aug 15;271(1):78-85. doi: 10.1016/j.taap.2013.04.025. Epub 2013 May 9.
• [8] lncRNAPCAT29 inhibits pulmonary fibrosis via the TGF?regulated RASAL1/ERK1/2 signal pathway.Mol Med Rep. 2018 Jun;17(6):7781-7788. doi: 10.3892/mmr.2018.8807. Epub 2018 Mar 28.
• [9] Germline alterations in RASAL1 in Cowden syndrome patients presenting with follicular thyroid cancer and in individuals with apparently sporadic epithelial thyroid cancer.J Clin Endocrinol Metab. 2014 Jul;99(7):E1316-21. doi: 10.1210/jc.2014-1225. Epub 2014 Apr 8.
• [10] Genomic Alterations of Anaplastic Thyroid Carcinoma Detected by Targeted Massive Parallel Sequencing in a BRAF(V600E) Mutation-Prevalent Area.Thyroid. 2016 May;26(5):683-90. doi: 10.1089/thy.2015.0506. Epub 2016 Apr 13.
• [11] EBP1 suppresses growth, migration, and invasion of thyroid cancer cells through upregulating RASAL expression.Tumour Biol. 2015 Nov;36(11):8325-31. doi: 10.1007/s13277-015-3523-y. Epub 2015 May 26.
• [12] Decreased expression of the RAS-GTPase activating protein RASAL1 is associated with colorectal tumor progression.Gastroenterology. 2009 Jan;136(1):206-16. doi: 10.1053/j.gastro.2008.09.063. Epub 2008 Oct 2.
• [13] A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification.Hum Pathol. 2016 Apr;50:70-8. doi: 10.1016/j.humpath.2015.11.012. Epub 2015 Dec 9.
• [14] 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.
• [15] Low-dose hydralazine prevents fibrosis in a murine model of acute kidney injury-to-chronic kidney disease progression.Kidney Int. 2017 Jan;91(1):157-176. doi: 10.1016/j.kint.2016.07.042. Epub 2016 Sep 28.
• [16] 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.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Transforming growth factor beta1 targets estrogen receptor signaling in bronchial epithelial cells. Respir Res. 2018 Aug 30;19(1):160. doi: 10.1186/s12931-018-0861-5.
• [19] 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.
• [20] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [21] Interleukin-19 as a translational indicator of renal injury. Arch Toxicol. 2015 Jan;89(1):101-6.
• [22] Temporal changes in gene expression in the skin of patients treated with isotretinoin provide insight into its mechanism of action. Dermatoendocrinol. 2009 May;1(3):177-87.
• [23] Gene expression profiling in Ishikawa cells: a fingerprint for estrogen active compounds. Toxicol Appl Pharmacol. 2009 Apr 1;236(1):85-96.
• [24] 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.
• [25] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.