Molecule Information

General Information of the Molecule (ID: Mol00514)

• Name: ATP-binding cassette sub-family C4 (ABCC4) ,Homo sapiens
• Synonyms: MRP/cMOAT-related ABC transporter; Multi-specific organic anion transporter B; MOAT-B; Multidrug resistance-associated protein 4; MOATB; MRP4
• Molecule Type: Protein
• Gene Name: ABCC4
• Gene ID: 10257
• Location: chr13:95019835-95301475[-]
• Sequence:
  MLPVYQEVKPNPLQDANLCSRVFFWWLNPLFKIGHKRRLEEDDMYSVLPEDRSQHLGEEL
  QGFWDKEVLRAENDAQKPSLTRAIIKCYWKSYLVLGIFTLIEESAKVIQPIFLGKIINYF
  ENYDPMDSVALNTAYAYATVLTFCTLILAILHHLYFYHVQCAGMRLRVAMCHMIYRKALR
  LSNMAMGKTTTGQIVNLLSNDVNKFDQVTVFLHFLWAGPLQAIAVTALLWMEIGISCLAG
  MAVLIILLPLQSCFGKLFSSLRSKTATFTDARIRTMNEVITGIRIIKMYAWEKSFSNLIT
  NLRKKEISKILRSSCLRGMNLASFFSASKIIVFVTFTTYVLLGSVITASRVFVAVTLYGA
  VRLTVTLFFPSAIERVSEAIVSIRRIQTFLLLDEISQRNRQLPSDGKKMVHVQDFTAFWD
  KASETPTLQGLSFTVRPGELLAVVGPVGAGKSSLLSAVLGELAPSHGLVSVHGRIAYVSQ
  QPWVFSGTLRSNILFGKKYEKERYEKVIKACALKKDLQLLEDGDLTVIGDRGTTLSGGQK
  ARVNLARAVYQDADIYLLDDPLSAVDAEVSRHLFELCICQILHEKITILVTHQLQYLKAA
  SQILILKDGKMVQKGTYTEFLKSGIDFGSLLKKDNEESEQPPVPGTPTLRNRTFSESSVW
  SQQSSRPSLKDGALESQDTENVPVTLSEENRSEGKVGFQAYKNYFRAGAHWIVFIFLILL
  NTAAQVAYVLQDWWLSYWANKQSMLNVTVNGGGNVTEKLDLNWYLGIYSGLTVATVLFGI
  ARSLLVFYVLVNSSQTLHNKMFESILKAPVLFFDRNPIGRILNRFSKDIGHLDDLLPLTF
  LDFIQTLLQVVGVVSVAVAVIPWIAIPLVPLGIIFIFLRRYFLETSRDVKRLESTTRSPV
  FSHLSSSLQGLWTIRAYKAEERCQELFDAHQDLHSEAWFLFLTTSRWFAVRLDAICAMFV
  IIVAFGSLILAKTLDAGQVGLALSYALTLMGMFQWCVRQSAEVENMMISVERVIEYTDLE
  KEAPWEYQKRPPPAWPHEGVIIFDNVNFMYSPGGPLVLKHLTALIKSQEKVGIVGRTGAG
  KSSLISALFRLSEPEGKIWIDKILTTEIGLHDLRKKMSIIPQEPVLFTGTMRKNLDPFNE
  HTDEELWNALQEVQLKETIEDLPGKMDTELAESGSNFSVGQRQLVCLARAILRKNQILII
  DEATANVDPRTDELIQKKIREKFAHCTVLTIAHRLNTIIDSDKIMVLDSGRLKEYDEPYV
  LLQNKESLFYKMVQQLGKAEAAALTETAKQVYFKRNYPHIGHTDHMVTNTSNGQPSTLTI
  FETAL
• Function: ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds and xenobiotics from cells. Transports a range of endogenous molecules that have a key role in cellular communication and signaling, including cyclic nucleotides such as cyclic AMP (cAMP) and cyclic GMP (cGMP), bile acids, steroid conjugates, urate, and prostaglandins. Mediates the ATP-dependent efflux of glutathione conjugates such as leukotriene C4 (LTC4) and leukotriene B4 (LTB4) too. The presence of GSH is necessary for the ATP-dependent transport of LTB4, whereas GSH is not required for the transport of LTC4. Mediates the cotransport of bile acids with reduced glutathione (GSH). Transports a wide range of drugs and their metabolites, including anticancer, antiviral and antibiotics molecules. Confers resistance to anticancer agents such as methotrexate.
• Uniprot ID: MRP4_HUMAN
• Ensembl ID: ENSG00000125257
• HGNC ID: HGNC:55

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Drug

Approved Drug(s) 4 drug(s) in total

Cilostazol

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Coronary artery disease [1]

• Sensitive Disease: Coronary artery disease [ICD-11: BA8Z.0]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Disease Class: Coronary artery disease [1]

• Sensitive Disease: Coronary artery disease [ICD-11: BA8Z.0]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Disease Class: Cerebral artery disease [1]

• Sensitive Disease: Cerebral artery disease [ICD-11: 8B26.2]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Disease Class: Cerebral artery disease [1]

• Sensitive Disease: Cerebral artery disease [ICD-11: 8B26.2]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Disease Class: Carotid artery disease [1]

• Sensitive Disease: Carotid artery disease [ICD-11: 8B10.Y]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Disease Class: Carotid artery disease [1]

• Sensitive Disease: Carotid artery disease [ICD-11: 8B10.Y]
• Sensitive Drug: Cilostazol
• Molecule Alteration: Function; Inhibition
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: JAK2 signaling pathway; Activation; hsa04917
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Mechanism Description: Cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. Mouse models of myocardial ischemia reperfusion have associated cilostazol with attenuation of multiple inflammatory markers through activation of PPAR gamma, JAK2, and STAT3 pathways

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Breast cancer [2]

• Sensitive Disease: Breast cancer [ICD-11: 2C60.3]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Inhibition; hsa05205
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: MCF-7 cells; Breast; Homo sapiens (Human); CVCL_0031
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay; Transwell assay; Scratch assay
• Mechanism Description: The combination of downregulation of ABCC4 with overexpression of miR-124-3p significantly increased sensitivity to ADR in MCF-7-ADR cells.

Intravenous immunoglobulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Kawasaki disease [3]

• Resistant Disease: Kawasaki disease [ICD-11: 4A44.5]
• Resistant Drug: Intravenous immunoglobulin
• Molecule Alteration: SNP; rs1751034
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Blood sample; .
• Experiment for Molecule Alteration: qRT-PCR
• Mechanism Description: Patients with 3-6 risk genotypes had significantly higher risk of IVIG resistance in KD than those with 0-2 risk genotypes, especially in children aged less than or equal to months and males. This is the first study in which MRP4 gene SNPs were found to be associated with IVIG resistance in KD.

Disease Class: Kawasaki disease [3]

• Resistant Disease: Kawasaki disease [ICD-11: 4A44.5]
• Resistant Drug: Intravenous immunoglobulin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The homozygous of MRP4 gene rs1751034 C allele is significantly associated with IVIG resistance in KD, especially in patients younger than 5 years old and boys.

Disease Class: Kawasaki disease [3]

• Resistant Disease: Kawasaki disease [ICD-11: 4A44.5]
• Resistant Drug: Intravenous immunoglobulin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Mechanism Description: The homozygous of MRP4 gene rs1751034 C allele is significantly associated with IVIG resistance in KD, especially in patients younger than 5 years old and boys.

Ivermectin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Disease Class: Pediculosis [4]

• Resistant Disease: Pediculosis [ICD-11: 1G00.0]
• Resistant Drug: Ivermectin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Pediculus humanus; 121225
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Disk diffusion assay
• Mechanism Description: Phylogenetic relatedness of P450 and ABC transporter genes over-transcribed following ivermectin exposure.Knockdown of CYP9AG2 P450 and ABCC4 transporter gene expression by RNA interference and subsequent increase in the sensitivity of lice to ivermectin.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Breast cancer [ICD-11: 2C60]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Breast tissue
• The Specified Disease: Breast cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.84E-05; Fold-change: 8.79E-02; Z-score: 1.77E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.71E-03; Fold-change: -4.95E-03; Z-score: -1.73E-02

ICD Disease Classification 11

Coronary artery disease [ICD-11: BA8Z]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Peripheral blood
• The Specified Disease: Coronary artery disease
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.62E-01; Fold-change: -1.57E-01; Z-score: -8.51E-01

References

• Ref 1: Cilostazol: a Review of Basic Mechanisms and Clinical Uses .Cardiovasc Drugs Ther. 2021 Apr 16. doi: 10.1007/s10557-021-07187-x. Online ahead of print. 10.1007/s10557-021-07187-x
• Ref 2: Dual-Targeting of miR-124-3p and ABCC4 Promotes Sensitivity to Adriamycin in Breast Cancer Cells. Genet Test Mol Biomarkers. 2019 Mar;23(3):156-165. doi: 10.1089/gtmb.2018.0259. Epub 2019 Feb 26.
• Ref 3: Homozygous of MRP4 Gene rs1751034 C Allele Is Related to Increased Risk of Intravenous Immunoglobulin Resistance in Kawasaki Disease .Front Genet. 2021 Mar 15;12:510350. doi: 10.3389/fgene.2021.510350. eCollection 2021. 10.3389/fgene.2021.510350
• Ref 4: Ivermectin: From theory to clinical application .Int J Antimicrob Agents. 2019 Aug;54(2):134-142. doi: 10.1016/j.ijantimicag.2019.05.003. Epub 2019 May 7. 10.1016/j.ijantimicag.2019.05.003