Molecule Information

General Information of the Molecule (ID: Mol00492)

• Name: E3 ubiquitin-protein ligase Mdm2 (MDM2) ,Homo sapiens
• Synonyms: Double minute 2 protein; Hdm2; Oncoprotein Mdm2; RING-type E3 ubiquitin transferase Mdm2; p53-binding protein Mdm2
• Molecule Type: Protein
• Gene Name: MDM2
• Gene ID: 4193
• Location: chr12:68808177-68845544[+]
• Sequence:
  MCNTNMSVPTDGAVTTSQIPASEQETLVRPKPLLLKLLKSVGAQKDTYTMKEVLFYLGQY
  IMTKRLYDEKQQHIVYCSNDLLGDLFGVPSFSVKEHRKIYTMIYRNLVVVNQQESSDSGT
  SVSENRCHLEGGSDQKDLVQELQEEKPSSSHLVSRPSTSSRRRAISETEENSDELSGERQ
  RKRHKSDSISLSFDESLALCVIREICCERSSSSESTGTPSNPDLDAGVSEHSGDWLDQDS
  VSDQFSVEFEVESLDSEDYSLSEEGQELSDEDDEVYQVTVYQAGESDTDSFEEDPEISLA
  DYWKCTSCNEMNPPLPSHCNRCWALRENWLPEDKGKDKGEISEKAKLENSTQAEEGFDVP
  DCKKTIVNDSRESCVEENDDKITQASQSQESEDYSQPSTSSSIIYSSQEDVKEFEREETQ
  DKEESVESSLPLNAIEPCVICQGRPKNGCIVHGKTGHLMACFTCAKKLKKRNKPCPVCRQ
  PIQMIVLTYFP
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome. Inhibits p53/TP53- and p73/TP73-mediated cell cycle arrest and apoptosis by binding its transcriptional activation domain. Also acts as a ubiquitin ligase E3 toward itself and ARRB1. Permits the nuclear export of p53/TP53. Promotes proteasome-dependent ubiquitin-independent degradation of retinoblastoma RB1 protein. Inhibits DAXX-mediated apoptosis by inducing its ubiquitination and degradation. Component of the TRIM28/KAP1-MDM2-p53/TP53 complex involved in stabilizing p53/TP53. Also component of the TRIM28/KAP1-ERBB4-MDM2 complex which links growth factor and DNA damage response pathways. Mediates ubiquitination and subsequent proteasome degradation of DYRK2 in nucleus. Ubiquitinates IGF1R and SNAI1 and promotes them to proteasomal degradation. Ubiquitinates DCX, leading to DCX degradation and reduction of the dendritic spine density of olfactory bulb granule cells. Ubiquitinates DLG4, leading to proteasomal degradation of DLG4 which is required for AMPA receptor endocytosis. Negatively regulates NDUFS1, leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. Binds NDUFS1 leading to its cytosolic retention rather than mitochondrial localization resulting in decreased supercomplex assembly (interactions between complex I and complex III), decreased complex I activity, ROS production, and apoptosis.
• Uniprot ID: MDM2_HUMAN
• Ensembl ID: ENSG00000135679
• HGNC ID: HGNC:6973

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 8 drug(s) in total

Cisplatin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Lung squamous cell carcinoma [1]

• Sensitive Disease: Lung squamous cell carcinoma [ICD-11: 2C25.3]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Sk-MES-1 cells; Lung; Homo sapiens (Human); CVCL_0630
• In Vitro Model: H157 cells; Lung; Homo sapiens (Human); CVCL_2458
• In Vitro Model: NCl-H226 cells; Lung; Homo sapiens (Human); CVCL_1544
• In Vitro Model: NCI-H522 cells; Lung; Homo sapiens (Human); CVCL_1567
• In Vitro Model: NCl-H1437 cells; Lung; Homo sapiens (Human); CVCL_1472
• In Vitro Model: NCl-H1792 cells; Lung; Homo sapiens (Human); CVCL_1495
• In Vitro Model: NCl-H1944 cells; Lung; Homo sapiens (Human); CVCL_1508
• In Vitro Model: NCl-H596 cells; Lung; Homo sapiens (Human); CVCL_1571
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoprecipitation assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: piR-L-138 directly interacted with p60-MDM2 and inhibited CDDP-activated apoptosis in p53-mutated LSCC.

Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [2]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-221 can activate the p53/mdm2 axis by inhibiting MDM2 and, in turn, p53 activation contributes to miR-221 enhanced expression. Moreover, by modulating the p53 axis, miR-221 impacts cell-cycle progression and apoptotic response to doxorubicin in hepatocellular carcinoma-derived cell lines.

LY2835219

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: LY2835219
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Approximately 20%-30% of breast cancer patients show overexpression of MDM2, and this overexpression contributes particularly to the progression of HR-positive breast cancer. It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence. Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Ovarian cancer [4]

• Resistant Disease: Ovarian cancer [ICD-11: 2C73.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: Hey A8 cells; Ovary; Homo sapiens (Human); CVCL_8878
• In Vitro Model: SkVO3ip1 cells; Ovary; Homo sapiens (Human); CVCL_0C84
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Down-regulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression.

Palbociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Palbociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Approximately 20%-30% of breast cancer patients show overexpression of MDM2, and this overexpression contributes particularly to the progression of HR-positive breast cancer. It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence. Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors.

Ribociclib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Breast cancer [3]

• Resistant Disease: Breast cancer [ICD-11: 2C60.3]
• Resistant Drug: Ribociclib
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Mechanism Description: Approximately 20%-30% of breast cancer patients show overexpression of MDM2, and this overexpression contributes particularly to the progression of HR-positive breast cancer. It is reported that CDK4/6 inhibitor-resistant cells have disrupted senescence pathways and insensitivity to the induction of senescence. Therefore, interruption of the senescence pathway by MDM2 in a p53-dependent manner may cause resistance to CDK4/6 inhibitors.

Sorafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hepatocellular carcinoma [5]

• Sensitive Disease: Hepatocellular carcinoma [ICD-11: 2C12.2]
• Sensitive Drug: Sorafenib
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: MDM2/AR-FkBP5/PHLPP signaling pathway; Regulation; hsa04115
• Cell Pathway Regulation: AKT/ERK signaling pathway; Regulation; hsa04010
• In Vitro Model: Huh-7 cells; Liver; Homo sapiens (Human); CVCL_0336
• In Vitro Model: HepG2 cells; Liver; Homo sapiens (Human); CVCL_0027
• In Vitro Model: SNU398 cells; Liver; Homo sapiens (Human); CVCL_0077
• In Vitro Model: Skhep1 cells; Liver; Homo sapiens (Human); CVCL_0525
• In Vitro Model: HA22T cells; Liver; Homo sapiens (Human); CVCL_7046
• In Vitro Model: SNU423 cells; Liver; Homo sapiens (Human); CVCL_0366
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: 3D Invasion Assay
• Mechanism Description: miR367-3p could increase AR expression via directly targeting the 3'UTR of MDM2 to decrease MDM2 protein expression. The resultant increase of AR expression might then promote the expression of FkBP5 and PHLPP, thus dephosphorylating and inactivating AkT and ERk, to suppress the HCC cell invasion. miR367-3p may function as an AR enhancer to increase Sorafenib chemotherapy efficacy via altering the MDM2/AR/FkBP5/PHLPP/(pAkT and pERk) signals to better suppress HCC metastasis.

Teniposide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Glioma [6]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Sensitive Drug: Teniposide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3'-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Brain cancer [ICD-11: 2A00]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Nervous tissue
• The Specified Disease: Brain cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.59E-23; Fold-change: 7.37E-02; Z-score: 3.63E-01
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.17E-01; Fold-change: 3.47E-01; Z-score: 1.21E+00
• The Studied Tissue: White matter
• The Specified Disease: Glioma
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.62E-04; Fold-change: 7.64E-01; Z-score: 1.66E+00
• The Studied Tissue: Brainstem tissue
• The Specified Disease: Neuroectodermal tumor
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.25E-02; Fold-change: -8.00E-03; Z-score: -3.55E-02

Liver cancer [ICD-11: 2C12]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Liver
• The Specified Disease: Liver cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.50E-04; Fold-change: 1.93E-01; Z-score: 5.64E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.41E-01; Fold-change: -1.42E-01; Z-score: -4.48E-01
• The Expression Level of Disease Section Compare with the Other Disease Section: p-value: 4.96E-01; Fold-change: 2.42E-02; Z-score: 1.06E-01

Lung cancer [ICD-11: 2C25]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Lung
• The Specified Disease: Lung cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.31E-13; Fold-change: 1.15E-01; Z-score: 4.36E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 9.70E-11; Fold-change: 1.87E-01; Z-score: 5.20E-01

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: 3.54E-23; Fold-change: 1.05E-01; Z-score: 5.51E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 2.48E-03; Fold-change: 8.91E-02; Z-score: 3.33E-01

Ovarian cancer [ICD-11: 2C73]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Ovary
• The Specified Disease: Ovarian cancer
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.89E-01; Fold-change: -6.93E-02; Z-score: -2.80E-01
• The Expression Level of Disease Section Compare with the Adjacent Tissue: p-value: 4.37E-01; Fold-change: -2.40E-01; Z-score: -4.79E-01

References

• Ref 1: A piRNA-like Small RNA Induces Chemoresistance to Cisplatin-Based Therapy by Inhibiting Apoptosis in Lung Squamous Cell Carcinoma. Mol Ther Nucleic Acids. 2017 Mar 17;6:269-278. doi: 10.1016/j.omtn.2017.01.003. Epub 2017 Jan 24.
• Ref 2: p53/mdm2 feedback loop sustains miR-221 expression and dictates the response to anticancer treatments in hepatocellular carcinoma. Mol Cancer Res. 2014 Feb;12(2):203-16. doi: 10.1158/1541-7786.MCR-13-0312-T. Epub 2013 Dec 9.
• Ref 3: Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review .Int J Cancer. 2019 Sep 1;145(5):1179-1188. doi: 10.1002/ijc.32020. Epub 2019 Jan 7. 10.1002/ijc.32020
• Ref 4: Downregulation of miR-194-5p induces paclitaxel resistance in ovarian cancer cells by altering MDM2 expression. Oncotarget. 2019 Jan 18;10(6):673-683. doi: 10.18632/oncotarget.26586. eCollection 2019 Jan 18.
• Ref 5: The miR-367-3p Increases Sorafenib Chemotherapy Efficacy to Suppress Hepatocellular Carcinoma Metastasis through Altering the Androgen Receptor Signals. EBioMedicine. 2016 Oct;12:55-67. doi: 10.1016/j.ebiom.2016.07.013. Epub 2016 Jul 14.
• Ref 6: MiR-181b sensitizes glioma cells to teniposide by targeting MDM2. BMC Cancer. 2014 Aug 25;14:611. doi: 10.1186/1471-2407-14-611.