Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT4IZ4TP)

• DOT Name: Large ribosomal subunit protein mL64 (GADD45GIP1)
• Synonyms: 39S ribosomal protein L59, mitochondrial; MRP-L59; CKII beta-associating protein; CR6-interacting factor 1; CRIF1; Growth arrest and DNA damage-inducible proteins-interacting protein 1; Papillomavirus L2-interacting nuclear protein 1; PLINP; PLINP-1; p53-responsive gene 6 protein
• Gene Name: GADD45GIP1
• Related Disease:
  Bone osteosarcoma
  Osteosarcoma
  Alzheimer disease
  Arthritis
  Breast carcinoma
  Neoplasm
  Prostate neoplasm
  Rheumatoid arthritis
  Hepatocellular carcinoma
  Acute myelogenous leukaemia
  Benign prostatic hyperplasia
  Iron-deficiency anemia
  leukaemia
  Leukemia
  Prostate cancer
  Prostate carcinoma
• UniProt ID: G45IP_HUMAN
• PDB ID: 3J7Y ; 3J9M ; 5OOL ; 5OOM ; 6I9R ; 6NU2 ; 6NU3 ; 6VLZ ; 6VMI ; 6ZM5 ; 6ZM6 ; 6ZS9 ; 6ZSA ; 6ZSB ; 6ZSC ; 6ZSD ; 6ZSE ; 6ZSG ; 7A5F ; 7A5G ; 7A5H ; 7A5I ; 7A5J ; 7A5K ; 7L08 ; 7L20 ; 7O9K ; 7O9M ; 7ODR ; 7ODS ; 7ODT ; 7OF0 ; 7OF2 ; 7OF3 ; 7OF4 ; 7OF5 ; 7OF6 ; 7OF7 ; 7OG4 ; 7OI6 ; 7OI7 ; 7OI8 ; 7OI9 ; 7OIA ; 7OIB ; 7OIC ; 7OID ; 7OIE ; 7PD3 ; 7PO4 ; 7QH6 ; 7QH7 ; 7QI4 ; 7QI5 ; 7QI6 ; 8ANY ; 8OIR ; 8OIT
• Pfam ID: PF10147
• Sequence:
  MAASVRQARSLLGVAATLAPGSRGYRARPPPRRRPGPRWPDPEDLLTPRWQLGPRYAAKQ
  FARYGAASGVVPGSLWPSPEQLRELEAEEREWYPSLATMQESLRVKQLAEEQKRREREQH
  IAECMAKMPQMIVNWQQQQRENWEKAQADKERRARLQAEAQELLGYQVDPRSARFQELLQ
  DLEKKERKRLKEEKQKRKKEARAAALAAAVAQDPAASGAPSS
• Function: Acts as a negative regulator of G1 to S cell cycle phase progression by inhibiting cyclin-dependent kinases. Inhibitory effects are additive with GADD45 proteins but occurs also in the absence of GADD45 proteins. Acts as a repressor of the orphan nuclear receptor NR4A1 by inhibiting AB domain-mediated transcriptional activity. May be involved in the hormone-mediated regulation of NR4A1 transcriptional activity. May play a role in mitochondrial protein synthesis.
• Tissue Specificity: Widely expressed. Highly expressed in the thyroid gland, heart, lymph nodes, trachea and adrenal tissues. Expressed at lower level in liver skeletal muscle, kidney, pancreas, testis, ovary and stomach. Barely detectable in adrenal adenoma and papillary thyroid cancer.
• Reactome Pathway:
  Mitochondrial translation elongation (R-HSA-5389840)
  Mitochondrial translation termination (R-HSA-5419276)
  Mitochondrial translation initiation (R-HSA-5368286)

Molecular Interaction Atlas (MIA) of This DOT

16 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Bone osteosarcoma	DIST1004	Definitive	Biomarker	[1]
Osteosarcoma	DISLQ7E2	Definitive	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Arthritis	DIST1YEL	Strong	Altered Expression	[3]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Prostate neoplasm	DISHDKGQ	Strong	Biomarker	[6]
Rheumatoid arthritis	DISTSB4J	Strong	Biomarker	[3]
Hepatocellular carcinoma	DIS0J828	moderate	Biomarker	[7]
Acute myelogenous leukaemia	DISCSPTN	Limited	Altered Expression	[8]
Benign prostatic hyperplasia	DISI3CW2	Limited	Biomarker	[9]
Iron-deficiency anemia	DIS0VQYF	Limited	Altered Expression	[8]
leukaemia	DISS7D1V	Limited	Biomarker	[8]
Leukemia	DISNAKFL	Limited	Biomarker	[8]
Prostate cancer	DISF190Y	Limited	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Large ribosomal subunit protein mL64 (GADD45GIP1).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Large ribosomal subunit protein mL64 (GADD45GIP1).	[11]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Large ribosomal subunit protein mL64 (GADD45GIP1).	[12]
Coumestrol	DM40TBU	Investigative	Coumestrol increases the expression of Large ribosomal subunit protein mL64 (GADD45GIP1).	[14]
CH-223191	DMMJZYC	Investigative	CH-223191 decreases the expression of Large ribosomal subunit protein mL64 (GADD45GIP1).	[15]

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 Large ribosomal subunit protein mL64 (GADD45GIP1).	[13]

References

• [1] CRIF1 as a potential target to improve the radiosensitivity of osteosarcoma.Proc Natl Acad Sci U S A. 2019 Oct 8;116(41):20511-20516. doi: 10.1073/pnas.1906578116. Epub 2019 Sep 23.
• [2] CR6-interacting factor 1 is a key regulator in A-induced mitochondrial disruption and pathogenesis of Alzheimer's disease.Cell Death Differ. 2015 Jun;22(6):959-73. doi: 10.1038/cdd.2014.184. Epub 2014 Nov 7.
• [3] CR6-interacting factor 1 controls autoimmune arthritis by regulation of signal transducer and activator of transcription 3 pathway and T helper type 17 cells.Immunology. 2019 Apr;156(4):413-421. doi: 10.1111/imm.13042. Epub 2019 Jan 28.
• [4] Breast cancer molecular signatures as determined by SAGE: correlation with lymph node status.Mol Cancer Res. 2007 Sep;5(9):881-90. doi: 10.1158/1541-7786.MCR-07-0055.
• [5] Nuclear lymphocyte-specific protein tyrosine kinase and its interaction with CR6-interacting factor 1 promote the survival of human leukemic T cells.Oncol Rep. 2015 Jul;34(1):43-50. doi: 10.3892/or.2015.3990. Epub 2015 May 19.
• [6] CR6-interacting factor 1 represses the transactivation of androgen receptor by direct interaction.Mol Endocrinol. 2008 Jan;22(1):33-46. doi: 10.1210/me.2007-0194. Epub 2007 Sep 20.
• [7] CR6-interacting factor 1 inhibits invasiveness by suppressing TGF--mediated epithelial-mesenchymal transition in hepatocellular carcinoma.Oncotarget. 2017 Oct 19;8(55):94759-94768. doi: 10.18632/oncotarget.21925. eCollection 2017 Nov 7.
• [8] CRIF1 interacting with CDK2 regulates bone marrow microenvironment-induced G0/G1 arrest of leukemia cells.PLoS One. 2014 Feb 10;9(2):e85328. doi: 10.1371/journal.pone.0085328. eCollection 2014.
• [9] Mechanism of androgen receptor corepression by CKBP2/CRIF1, a multifunctional transcription factor coregulator expressed in prostate cancer.Mol Cell Endocrinol. 2014 Jan 25;382(1):302-313. doi: 10.1016/j.mce.2013.09.036. Epub 2013 Oct 5.
• [10] 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.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [13] 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.
• [14] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [15] Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. Toxicol Lett. 2018 Aug;292:162-174.