Details of Host Protein-DME Interaction (HOSPPI)

General Information of Drug-Metabolizing Enzyme (DME ID: DME0124)
DME Name	Nitric oxide synthase inducible (NOS2), Homo sapiens	DME Info
UniProt ID	NOS2_HUMAN
EC Number	EC: 1.14.13.39 (Click to Show/Hide the Complete EC Tree) Oxidoreductase Oxygen paired donor oxidoreductase NADH/NADPH donor oxidoreductase EC: 1.14.13.39
Lineage	Species: Homo sapiens (Click to Show/Hide the Complete Species Lineage) Kingdom: Metazoa Phylum: Chordata Class: Mammalia Order: Primates Family: Hominidae Genus: Homo Species: Homo sapiens
Interactome

Disease Specific Interactions between Host Protein and DME (HOSPPI)
ICD Disease Classification Healthy
ICD-11: Healthy		Click to Show/Hide the Full List of HOSPPI: 6 HOSPPI
Transcription-factor regulation
I-kappa-B-alpha (NFKBIA)		Health		Repression
Uniprot ID	IKBA_HUMAN
Interaction Name	NFKBIA-NOS2 interaction				[2]
Studied Cell Lines	Human intimal smooth muscle cell line
Description	I-kappa-B-alpha (NFKBIA) is reported to repress the transcription of NOS2 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between NFKBIA and NOS2 can repress the drug-metabolizing process of Nitric oxide synthase inducible.
I-kappa-B-kinase beta (IKBKB)		Health		Repression
Uniprot ID	IKKB_HUMAN
Interaction Name	IKBKB-NOS2 interaction				[2]
Studied Cell Lines	Human intimal smooth muscle cell line
Description	I-kappa-B-kinase beta (IKBKB) is reported to repress the transcription of NOS2 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between IKBKB and NOS2 can repress the drug-metabolizing process of Nitric oxide synthase inducible.
Krueppel-like factor 6 (KLF6)		Health		Activation
Uniprot ID	KLF6_HUMAN
Interaction Name	KLF6-NOS2 interaction				[3]
Studied Cell Lines	COS-7 and Jurkat cell lines
Ensembl ID	ENSG00000067082
Description	Krueppel-like factor 6 (KLF6) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between KLF6 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Nuclear factor kappa-B p105 (NFKB1)		Health		Activation
Uniprot ID	NFKB1_HUMAN
Interaction Name	NFKB1-NOS2 interaction				[4], [5], [6]
Studied Cell Lines	Human umbilical endothelial cell line
Ensembl ID	ENSG00000109320
Description	Nuclear factor kappa-B p105 (NFKB1) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between NFKB1 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Transcription factor p65 (RELA)		Health		Activation
Uniprot ID	TF65_HUMAN
Interaction Name	RELA-NOS2 interaction				[4], [5], [6]
Studied Cell Lines	Human umbilical endothelial cell line
Ensembl ID	ENSG00000173039
Description	Transcription factor p65 (RELA) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between RELA and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Histone modification
Histone deacetylases (HDACs)		Health		Repression
Uniprot ID	HDAC1_HUMAN
Interaction Name	HDACs-NOS2 interaction				[1]
Studied Cell Lines	Microglial cell line
Description	Histone deacetylases (HDACs) are reported to deacetylate the NOS2 gene and thereby repress the transcriptional activity of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between HDACs and NOS2 can inhibit the drug-metabolizing process of Nitric oxide synthase inducible.
ICD Disease Classification 02 Neoplasms
ICD-11: 2A00 Brain cancer		Click to Show/Hide the Full List of HOSPPI: 3 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Brain neuroblastoma		Significant hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypomethylation p-value: 1.52E-11; delta-beta: -3.35E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hypo-methylate the NOS2 gene, which leads to a significantly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can significantly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
DNA methyltransferase (DNMT)		Cerebellar liponeurocytoma		Significant hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypomethylation p-value: 1.37E-04; delta-beta: -4.52E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hypo-methylate the NOS2 gene, which leads to a significantly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can significantly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
DNA methyltransferase (DNMT)		Third ventricle chordoid glioma		Significant hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypomethylation p-value: 3.40E-03; delta-beta: -3.50E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hypo-methylate the NOS2 gene, which leads to a significantly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can significantly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2A01 Meningeal tumour		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Meningioma		Moderate hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Moderate hypomethylation p-value: 1.19E-36; delta-beta: -2.59E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the NOS2 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can moderatly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2B30 Lymphoma		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Lymphoma		Moderate hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Moderate hypomethylation p-value: 6.65E-07; delta-beta: -2.18E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the NOS2 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can moderatly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD-11: 2B90 Colorectal cancer		Click to Show/Hide the Full List of HOSPPI: 3 HOSPPI
Transcription-factor regulation
Adenomatous polyposis coli (APC)		Colorectal cancer		Activation
Uniprot ID	APC_HUMAN
Interaction Name	APC-NOS2 interaction				[7]
Studied Cell Lines	Colorectal adenocarcinomas cell line
Description	Adenomatous polyposis coli (APC) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between APC and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Proto-oncogene c-Fos (FOS)		Colorectal cancer		Repression
Uniprot ID	FOS_HUMAN
Interaction Name	FOS-NOS2 interaction				[8]
Studied Cell Lines	Human epithelial-like DLD-I cell line
Ensembl ID	ENSG00000170345
Description	Proto-oncogene c-Fos (FOS) is reported to repress the transcription of NOS2 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between FOS and NOS2 can repress the drug-metabolizing process of Nitric oxide synthase inducible.
Transcription factor AP-1 (JUN)		Colorectal cancer		Repression
Uniprot ID	JUN_HUMAN
Interaction Name	JUN-NOS2 interaction				[8]
Studied Cell Lines	Human epithelial-like DLD-I cell line
Ensembl ID	ENSG00000177606
Description	Transcription factor AP-1 (JUN) is reported to repress the transcription of NOS2 gene, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between JUN and NOS2 can repress the drug-metabolizing process of Nitric oxide synthase inducible.
ICD-11: 2C12 Liver cancer		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
Transcription-factor regulation
Metastasis-associated MTA1 (MTA1)		Liver cancer		Activation
Uniprot ID	MTA1_HUMAN
Interaction Name	MTA1-NOS2 interaction				[9]
Studied Cell Lines	HepG2 cell line
Ensembl ID	ENSG00000182979
Description	Metastasis-associated MTA1 (MTA1) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between MTA1 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
DNA methylation
DNA methyltransferase (DNMT)		Liver cancer		Significant hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Significant hypomethylation p-value: 8.33E-10; delta-beta: -3.16E-01
Description	DNA methyltransferase (DNMT) is reported to significantly hypo-methylate the NOS2 gene, which leads to a significantly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can significantly affect the drug-metabolizing process of Nitric oxide synthase inducible.
The Methylation Level of Disease Section Compare with the Adjacent Tissue	Moderate hypomethylation p-value: 3.80E-04; delta-beta: -2.28E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the NOS2 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can moderatly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue adjacent to the diseased tissue of patients DME methylation in the normal tissue of healthy individuals DME methylation in tissue other than the diseased tissue of patients
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data of patients in the normal section of the tissue adjacent to the disease section Download DME methylation data in the tissue of healthy individual Download DME methylation data in the tissue of the other disease section
ICD-11: 2C25 Lung cancer		Click to Show/Hide the Full List of HOSPPI: 4 HOSPPI
Transcription-factor regulation
Fos-related antigen 2 (FOSL2)		Lung cancer		Activation
Uniprot ID	FOSL2_HUMAN
Interaction Name	FOSL2-NOS2 interaction				[10]
Studied Cell Lines	Human airway epithelial cell line, 293T and A549 cell lines
Ensembl ID	ENSG00000075426
Description	Fos-related antigen 2 (FOSL2) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between FOSL2 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Proto-oncogene c-Fos (FOS)		Lung cancer		Activation
Uniprot ID	FOS_HUMAN
Interaction Name	FOS-NOS2 interaction				[10]
Studied Cell Lines	Human airway epithelial cell line, 293T and A549 cell lines
Ensembl ID	ENSG00000170345
Description	Proto-oncogene c-Fos (FOS) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between FOS and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
TF factor jun-D (JUND)		Lung cancer		Activation
Uniprot ID	JUND_HUMAN
Interaction Name	JUND-NOS2 interaction				[10]
Studied Cell Lines	Human airway epithelial cell line, 293T and A549 cell lines
Ensembl ID	ENSG00000130522
Description	TF factor jun-D (JUND) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between JUND and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
Transcription factor AP-1 (JUN)		Lung cancer		Activation
Uniprot ID	JUN_HUMAN
Interaction Name	JUN-NOS2 interaction				[10]
Studied Cell Lines	Human airway epithelial cell line, 293T and A549 cell lines
Ensembl ID	ENSG00000177606
Description	Transcription factor AP-1 (JUN) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between JUN and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
ICD-11: 2D50 Brain cancer metastasis		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
DNA methylation
DNA methyltransferase (DNMT)		Posterior fossa ependymoma		Moderate hypomethylation
Interaction Name	DNMT-NOS2 interaction
The Methylation Level of Disease Section Compare with the Healthy Individual Tissue	Moderate hypomethylation p-value: 1.34E-96; delta-beta: -2.54E-01
Description	DNA methyltransferase (DNMT) is reported to moderatly hypo-methylate the NOS2 gene, which leads to a moderatly increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between DNMT and NOS2 can moderatly affect the drug-metabolizing process of Nitric oxide synthase inducible.
DME methylation in the diseased tissue of patients DME methylation in the normal tissue of healthy individuals
Violin Diagram of DME Disease-specific Methylation Level			Click to View the Clearer Original Diagram
Download DME methylation barchart for all samples Download DME methylation data of patients in the disease section of the tissue Download DME methylation data in the tissue of healthy individual
ICD Disease Classification 11 Circulatory system diseases
ICD-11: BA6Z Myocardial ischemia		Click to Show/Hide the Full List of HOSPPI: 2 HOSPPI
Transcription-factor regulation
STAT 1-alpha/beta (STAT1)		Myocardial ischemia/reperfusion injury		Activation
Uniprot ID	STAT1_HUMAN
Interaction Name	STAT1-NOS2 interaction				[11]
Studied Cell Lines	Myocardial ischemia/reperfusion injury cell line
Ensembl ID	ENSG00000115415
Description	STAT 1-alpha/beta (STAT1) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between STAT1 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
STAT 2 (STAT2)		Myocardial ischemia/reperfusion injury		Activation
Uniprot ID	STAT2_HUMAN
Interaction Name	STAT2-NOS2 interaction				[11]
Studied Cell Lines	Myocardial ischemia/reperfusion injury cell line
Ensembl ID	ENSG00000170581
Description	STAT 2 (STAT2) is reported to activate the transcription of NOS2 gene, which leads to an increased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible. As a result, the interaction between STAT2 and NOS2 can activate the drug-metabolizing process of Nitric oxide synthase inducible.
ICD Disease Classification 15 Musculoskeletal system diseases
ICD-11: FA00 Osteoarthritis		Click to Show/Hide the Full List of HOSPPI: 1 HOSPPI
Non-coding RNA regulation
hsa-miR-26a-5p		Osteoarthritis		Suppression
miRBase ID	MIMAT0000082
Interaction Name	hsa-miR-26a-5p--NOS2 regulation				[12]
Studied Cell Lines	Osteoarthritis chondrocytes
Description	hsa-miR-26a-5p is reported to suppress NOS2 mRNA translation by binding to the 3' untranslated region (3'UTR) of NOS2 mRNA, which leads to a decreased expression of the drug-metabolizing enzyme Nitric oxide synthase inducible.

References
1	Liver X receptor-dependent inhibition of microglial nitric oxide synthase 2. J Neuroinflammation. 2015 Feb 10;12:27.
2	Histamine upregulates the expression of inducible nitric oxide synthase in human intimal smooth muscle cells via histamine H1 receptor and NF-kappaB signaling pathway. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1556-61.
3	Transcriptional activation of the human inducible nitric-oxide synthase promoter by Kruppel-like factor 6. J Biol Chem. 2003 Apr 25;278(17):14812-9.
4	Angiotensin II up-regulates expression of inducible nitric oxide synthase in human umbilical endothelial cells: roles of AT1 and AT2. Zhonghua Xin Xue Guan Bing Za Zhi. 2006 Jul;34(7):647-50.
5	NOS2 regulation of NF-kappaB by S-nitrosylation of p65. J Biol Chem. 2007 Oct 19;282(42):30667-72.
6	Inhibition of LPS-induced iNOS, COX-2 and cytokines expression by poncirin through the NF-kappaB inactivation in RAW 264.7 macrophage cells. Biol Pharm Bull. 2007 Dec;30(12):2345-51.
7	Nitric oxide synthase 2 mRNA expression in relation to p53 and adenomatous polyposis coli mutations in primary colorectal adenocarcinomas. Surgery. 2002 Apr;131(4):384-92.
8	Cytokine Induction of NO Synthase II in Human DLD-1 Cells: Roles of the JAK-STAT, AP-1 and NF-kappaB-signaling Pathways Br J Pharmacol. 1998 Sep;125(1):193-201.
9	Stimulation of inducible nitric oxide by hepatitis B virus transactivator protein HBx requires MTA1 coregulator. J Biol Chem. 2010 Mar 5;285(10):6980-6.
10	STAT-1 and c-Fos interaction in nitric oxide synthase-2 gene activation. Am J Physiol Lung Cell Mol Physiol. 2003 Jul;285(1):L137-48.
11	Role of the JAK-STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc Med. 2003 Feb;13(2):72-9.
12	MicroRNA-26a-5p regulates the expression of inducible nitric oxide synthase via activation of NF-KappaB pathway in human osteoarthritis chondrocytes. Arch Biochem Biophys. 2016 Mar 15;594:61-7.

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