Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPOMM5J)

• DOT Name: GTPase RhebL1 (RHEBL1)
• Synonyms: Ras homolog enriched in brain like-1 c; RhebL1c; Ras homolog enriched in brain-like protein 1; Rheb-like protein 1; Rheb2
• Gene Name: RHEBL1
• Related Disease:
  Acute myelogenous leukaemia
  Clear cell renal carcinoma
  Autoimmune disease
• UniProt ID: REBL1_HUMAN
• PDB ID: 3OES
• Pfam ID: PF00071
• Sequence:
  MPLVRYRKVVILGYRCVGKTSLAHQFVEGEFSEGYDPTVENTYSKIVTLGKDEFHLHLVD
  TAGQDEYSILPYSFIIGVHGYVLVYSVTSLHSFQVIESLYQKLHEGHGKTRVPVVLVGNK
  ADLSPEREVQAVEGKKLAESWGATFMESSARENQLTQGIFTKVIQEIARVENSYGQERRC
  HLM
• Function: Binds GTP and exhibits intrinsic GTPase activity. May activate NF-kappa-B-mediated gene transcription. Promotes signal transduction through MTOR, activates RPS6KB1, and is a downstream target of the small GTPase-activating proteins TSC1 and TSC2.
• Tissue Specificity: Ubiquitously expressed. Expression increased at least 2-fold in several tumor cell lines.

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Altered Expression	[1]
Clear cell renal carcinoma	DISBXRFJ	Strong	Altered Expression	[2]
Autoimmune disease	DISORMTM	moderate	Biomarker	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of GTPase RhebL1 (RHEBL1).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of GTPase RhebL1 (RHEBL1).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of GTPase RhebL1 (RHEBL1).	[6]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of GTPase RhebL1 (RHEBL1).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the expression of GTPase RhebL1 (RHEBL1).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of GTPase RhebL1 (RHEBL1).	[4]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of GTPase RhebL1 (RHEBL1).	[11]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of GTPase RhebL1 (RHEBL1).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of GTPase RhebL1 (RHEBL1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of GTPase RhebL1 (RHEBL1).	[10]

References

• [1] DHH-RHEBL1 fusion transcript: a novel recurrent feature in the new landscape of pediatric CBFA2T3-GLIS2-positive acute myeloid leukemia.Oncotarget. 2013 Oct;4(10):1712-20. doi: 10.18632/oncotarget.1280.
• [2] Activation of the mTOR signaling pathway in renal clear cell carcinoma.J Urol. 2007 Jan;177(1):346-52. doi: 10.1016/j.juro.2006.08.076.
• [3] Amino Acids License Kinase mTORC1 Activity and Treg Cell Function via Small G Proteins Rag and Rheb.Immunity. 2019 Dec 17;51(6):1012-1027.e7. doi: 10.1016/j.immuni.2019.10.001. Epub 2019 Oct 24.
• [4] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [7] 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.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] 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.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.