Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIRV97L)

• DOT Name: Zinc finger protein GLI2 (GLI2)
• Synonyms: GLI family zinc finger protein 2; Tax helper protein
• Gene Name: GLI2
• Related Disease:
  Holoprosencephaly 9
  Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome
  Combined pituitary hormone deficiencies, genetic form
  Holoprosencephaly
• UniProt ID: GLI2_HUMAN
• Pfam ID: PF00096
• Sequence:
  METSASATASEKQEAKSGILEAAGFPDPGKKASPLVVAAAAAAAVAAQGVPQHLLPPFHA
  PLPIDMRHQEGRYHYEPHSVHGVHGPPALSGSPVISDISLIRLSPHPAGPGESPFNAPHP
  YVNPHMEHYLRSVHSSPTLSMISAARGLSPADVAQEHLKERGLFGLPAPGTTPSDYYHQM
  TLVAGHPAPYGDLLMQSGGAASAPHLHDYLNPVDVSRFSSPRVTPRLSRKRALSISPLSD
  ASLDLQRMIRTSPNSLVAYINNSRSSSAASGSYGHLSAGALSPAFTFPHPINPVAYQQIL
  SQQRGLGSAFGHTPPLIQPSPTFLAQQPMALTSINATPTQLSSSSNCLSDTNQNKQSSES
  AVSSTVNPVAIHKRSKVKTEPEGLRPASPLALTQGQVSGHGSCGCALPLSQEQLADLKED
  LDRDDCKQEAEVVIYETNCHWEDCTKEYDTQEQLVHHINNEHIHGEKKEFVCRWQACTRE
  QKPFKAQYMLVVHMRRHTGEKPHKCTFEGCSKAYSRLENLKTHLRSHTGEKPYVCEHEGC
  NKAFSNASDRAKHQNRTHSNEKPYICKIPGCTKRYTDPSSLRKHVKTVHGPDAHVTKKQR
  NDVHLRTPLLKENGDSEAGTEPGGPESTEASSTSQAVEDCLHVRAIKTESSGLCQSSPGA
  QSSCSSEPSPLGSAPNNDSGVEMPGTGPGSLGDLTALDDTPPGADTSALAAPSAGGLQLR
  KHMTTMHRFEQLKKEKLKSLKDSCSWAGPTPHTRNTKLPPLPGSGSILENFSGSGGGGPA
  GLLPNPRLSELSASEVTMLSQLQERRDSSTSTVSSAYTVSRRSSGISPYFSSRRSSEASP
  LGAGRPHNASSADSYDPISTDASRRSSEASQCSGGSGLLNLTPAQQYSLRAKYAAATGGP
  PPTPLPGLERMSLRTRLALLDAPERTLPAGCPRPLGPRRGSDGPTYGHGHAGAAPAFPHE
  APGGGARRASDPVRRPDALSLPRVQRFHSTHNVNPGPLPPCADRRGLRLQSHPSTDGGLA
  RGAYSPRPPSISENVAMEAVAAGVDGAGPEADLGLPEDDLVLPDDVVQYIKAHASGALDE
  GTGQVYPTESTGFSDNPRLPSPGLHGQRRMVAADSNVGPSAPMLGGCQLGFGAPSSLNKN
  NMPVQWNEVSSGTVDALASQVKPPPFPQGNLAVVQQKPAFGQYPGYSPQGLQASPGGLDS
  TQPHLQPRSGAPSQGIPRVNYMQQLRQPVAGSQCPGMTTTMSPHACYGQVHPQLSPSTIS
  GALNQFPQSCSNMPAKPGHLGHPQQTEVAPDPTTMGNRHRELGVPDSALAGVPPPHPVQS
  YPQQSHHLAASMSQEGYHQVPSLLPARQPGFMEPQTGPMGVATAGFGLVQPRPPLEPSPT
  GRHRGVRAVQQQLAYARATGHAMAAMPSSQETAEAVPKGAMGNMGSVPPQPPPQDAGGAP
  DHSMLYYYGQIHMYEQDGGLENLGSCQVMRSQPPQPQACQDSIQPQPLPSPGVNQVSSTV
  DSQLLEAPQIDFDAIMDDGDHSSLFSGALSPSLLHSLSQNSSRLTTPRNSLTLPSIPAGI
  SNMAVGDMSSMLTSLAEESKFLNMMT
• Function: Functions as a transcription regulator in the hedgehog (Hh) pathway. Functions as a transcriptional activator. May also function as transcriptional repressor. Requires STK36 for full transcriptional activator activity. Required for normal embryonic development ; [Isoform 1]: Involved in the smoothened (SHH) signaling pathway; [Isoform 2]: Involved in the smoothened (SHH) signaling pathway; [Isoform 3]: Involved in the smoothened (SHH) signaling pathway; [Isoform 4]: Involved in the smoothened (SHH) signaling pathway; [Isoform 1]: Acts as a transcriptional activator in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 ; [Isoform 2]: (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 ; [Isoform 3]: (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 ; [Isoform 4]: (Microbial infection) Acts as a transcriptional activators in T-cell leukemia virus type 1 (HTLV-1)-infected cells in a Tax-dependent manner. Binds to the DNA sequence 5'-GAACCACCCA-3' which is part of the Tax-responsive element (TRE-2S) regulatory element that augments the Tax-dependent enhancer of HTLV-1 ; [Isoform 5]: Acts as a transcriptional repressor.
• Tissue Specificity: Expressed in breast cancers (at protein level) . Isoform 1 and isoform 4 are expressed in HTLV-1-infected T-cell lines (at protein level) . Isoform 1 and isoform 2 are strongly expressed in HTLV-1-infected T-cell lines . Isoform 3 and isoform 4 are weakly expressed in HTLV-1-infected T-cell lines .
• KEGG Pathway:
  Hedgehog sig.ling pathway (hsa04340)
  Hippo sig.ling pathway (hsa04390)
  Pathways in cancer (hsa05200)
  Basal cell carcinoma (hsa05217)
• Reactome Pathway:
  Hedgehog 'off' state (R-HSA-5610787)
  Hedgehog 'on' state (R-HSA-5632684)
  GLI proteins bind promoters of Hh responsive genes to promote transcription (R-HSA-5635851)
  RUNX2 regulates chondrocyte maturation (R-HSA-8941284)
  Degradation of GLI2 by the proteasome (R-HSA-5610783)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Holoprosencephaly 9	DIS1FXHU	Definitive	Autosomal dominant	[1]
Postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome	DIST3CZX	Definitive	Autosomal dominant	[2]
Combined pituitary hormone deficiencies, genetic form	DISW6YL6	Supportive	Autosomal dominant	[3]
Holoprosencephaly	DISR35EC	Supportive	Autosomal recessive	[4]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
LDE225	DMM9F25	Phase 2	Zinc finger protein GLI2 (GLI2) decreases the response to substance of LDE225.	[30]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Zinc finger protein GLI2 (GLI2).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Zinc finger protein GLI2 (GLI2).	[6]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Zinc finger protein GLI2 (GLI2).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Zinc finger protein GLI2 (GLI2).	[8]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Zinc finger protein GLI2 (GLI2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Zinc finger protein GLI2 (GLI2).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Zinc finger protein GLI2 (GLI2).	[12]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Zinc finger protein GLI2 (GLI2).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Zinc finger protein GLI2 (GLI2).	[14]
Marinol	DM70IK5	Approved	Marinol increases the expression of Zinc finger protein GLI2 (GLI2).	[15]
Selenium	DM25CGV	Approved	Selenium increases the expression of Zinc finger protein GLI2 (GLI2).	[16]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Zinc finger protein GLI2 (GLI2).	[17]
Gemcitabine	DMSE3I7	Approved	Gemcitabine affects the expression of Zinc finger protein GLI2 (GLI2).	[18]
Vismodegib	DM5IXKQ	Approved	Vismodegib decreases the expression of Zinc finger protein GLI2 (GLI2).	[19]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Zinc finger protein GLI2 (GLI2).	[16]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Zinc finger protein GLI2 (GLI2).	[20]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Zinc finger protein GLI2 (GLI2).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Zinc finger protein GLI2 (GLI2).	[22]
EMBELIN	DMFZO4Y	Terminated	EMBELIN decreases the expression of Zinc finger protein GLI2 (GLI2).	[23]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Zinc finger protein GLI2 (GLI2).	[25]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Zinc finger protein GLI2 (GLI2).	[26]
GALLICACID	DM6Y3A0	Investigative	GALLICACID decreases the expression of Zinc finger protein GLI2 (GLI2).	[27]
crotylaldehyde	DMTWRQI	Investigative	crotylaldehyde decreases the expression of Zinc finger protein GLI2 (GLI2).	[29]

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 Zinc finger protein GLI2 (GLI2).	[10]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Zinc finger protein GLI2 (GLI2).	[24]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
D-glucose	DMMG2TO	Investigative	D-glucose affects the localization of Zinc finger protein GLI2 (GLI2).	[28]

References

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• [3] Novel heterozygous nonsense GLI2 mutations in patients with hypopituitarism and ectopic posterior pituitary lobe without holoprosencephaly. J Clin Endocrinol Metab. 2010 Nov;95(11):E384-91. doi: 10.1210/jc.2010-1050. Epub 2010 Aug 4.
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