2. Signaling Pathways
  3. Apoptosis
  4. MDM-2/p53

MDM-2/p53

MDM-2/p53

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The p53 tumor suppressor is a principal mediator of growth arrest, senescence, and apoptosis in response to a broad array of cellular damage. p53 is a short-lived protein that is maintained at low, often undetectable, levels in normal cells. Under stress conditions, the p53 protein accumulates in the cell, binds in its tetrameric form to p53-response elements and induces the transcription of various genes.

MDM-2 is transcriptionally activated by p53 and MDM-2, in turn, inhibits p53 activity in several ways. MDM-2 binds to the p53 transactivation domain and thereby inhibits p53-mediated transactivation. MDM-2 also contains a signal sequence that is similar to the nuclear export signal of various viral proteins and, after binding to p53, it induces its nuclear export. As p53 is a transcription factor, it needs to be in the nucleus to be able to access the DNA; its transport to the cytoplasm by MDM-2 prevents this. Finally, MDM-2 is a ubiquitin ligase, so is able to target p53 for degradation by the proteasome.

In many tumors p53 is inactivated by the overexpression of the negative regulators MDM2 and MDM4 or by the loss of activity of the MDM2 inhibitor ARF. The pathway can be reactivated in these tumors by small molecules that inhibit the interaction of MDM2 and/or MDM4 with p53. Such molecules are now in clinical trials.

Cat. No. Product Name Effect Purity Chemical Structure
  • HY-N0331R
    Ziyuglycoside I (Standard)
    		p53 Activator
    Ziyuglycoside I (Standard) is the analytical standard of Ziyuglycoside I. This product is intended for research and analytical applications. Ziyuglycoside I isolated from S. officinalis root, has anti-wrinkle activity, and increases the expression of type I collagen. Ziyuglycoside I could be used as an active ingredient for cosmetics. Ziyuglycoside I triggers cell cycle arrest and apoptosis mediated by p53, it can be a potential agent candidate for treating triple-negative breast cancer (TNBC).
    Ziyuglycoside I (Standard)
  • HY-182245
    Anticancer agent 314
    Anticancer agent 314 is a multi-target anticancer agent with tubulin polymerization inhibitory activity (IC50 = 6.35 μM) and human carbonic anhydrase IX (Ki = 27.1 nM) and XII (Ki 20.9 = nM) inhibitory activity. Anticancer agent 314 binds to the colchicine-binding pocket of tubulin and inhibits tumor-associated carbonic anhydrase isoforms via zinc coordination within enzyme active sites. Anticancer agent 314 induces G2/M phase cell cycle arrest, apoptosis via p53-dependent signaling, and broad-spectrum antiproliferative activity across multiple cancer cells. Anticancer agent 314 can be used for the research of cancer, such as leukemia, melanoma, ovarian cancer.
    Anticancer agent 314
  • HY-173074
    Microtubulin-IN-1
    		p53 Activator
    Microtubulin-IN-1 (Compound 8g) is the inhibitor for microtubulin that targets colchicine-binding site, disrupts the microtubulin integrity, and induces the upregulation of p53. Microtubulin-IN-1 exhibits antiproliferative activity in a variety of cancer cell lines (IC50 for NCI-H460, BxPC-3 and HT-29 is 2.4, 1.6 and 2.07 nM, respectively), arrests the cell cycle at G2/M phase, and induces apoptosis in NCI-H460.
    Microtubulin-IN-1
  • HY-180619
    p53 Y220C ligand-1
    		Ligand
    p53 Y220C ligand-1(compound PK-A) is a target protein ligand of p53 DUBTAC modulator-1 (HY-180618). p53 Y220C ligand-1 exhibits potent activity in inhibiting cell proliferation in Huh7 cells.
    p53 Y220C ligand-1
  • HY-172597
    YL-1-9
    		Inhibitor
    YL-1-9 is an inhibitor of the degradation of p53 by MDM2 through strong binding to the key hydrophobic pockets of MDM2. YL-1-9 induces cell cycle arrest and apoptosis in breast cancer cells.
    YL-1-9
  • HY-W011434R
    Triglycidyl isocyanurate (Standard)
    		p53 Activator
    Triglycidyl isocyanurate (Standard) is the analytical standard of Triglycidyl isocyanurate. This product is intended for research and analytical applications. Triglycidyl isocyanurate (TGIC; Teroxirone) is a triazene triepoxide with antiangiogenic and antineoplastic activities. Triglycidyl isocyanurate inhibits the growth of non-small-cell-lung cancer cells via?p53 activation. Triglycidyl isocyanurate induces cell apoptosis. Triglycidyl isocyanurate can be used for cancer research.
    Triglycidyl isocyanurate (Standard)
  • HY-122860
    SKLB-C05
    		Activator
    SKLB-C05 is a novel selective, orally active TOPK inhibitor, with an IC50 of 0.5 nM. SKLB-C05 selectively inhibit TOPK kinase. SKLB-C05 induces Apoptosis, downregulates c-Myc, γ-H2AX, activates p53, blocks FAK/Src medicated migration-related signaling. SKLB-C05 disturbs cell mitosis. SKLB-C05 shows anticancer activity only against TOPK-positive colorectal cancer.
    SKLB-C05
  • HY-177208
    BW-AQ-113
    		p53 Activator
    BW-AQ-113 is an Anthraquinone (HY-N0354) derivative. BW-AQ-113 can specifically degrade MDM2 and activate the p53 pathway. BW-AQ-113 can induce apoptosis by downregulating anti-apoptotic gene Bcl-2 and regulating pro-apoptotic gene Bax and CASP3. BW-AQ-113 can be used for research of p53 wild-type hematological malignancies.
    BW-AQ-113
  • HY-124791
    MMRi6
    		Inhibitor 99.70%
    MMRi6 is a Mdm2-MdmX RING domain inhibitor that can disrupt Mdm2-MdmX RING-RING interaction in vitro. MMRi6 inhibits MdmX-stimulated Mdm2 autoubiquitination and Mdm2-MdmX-mediated p53 polyubiquitination in vitro without affecting NEDD4-1 autoubiquitination. MMRi6 induces p53 stabilization and accumulation and induces PARP cleavage in wt-p53 Emu-myc lymphoma cells. MMRi6 inhibits the growth of wt-p53 and p53-null Emu-myc lymphoma cells with IC50s of approximately 0.5 μM and 3 μM, respectively. MMRi6 can be used for the study of leukemia/lymphoma.
    MMRi6
  • HY-148640
    WK500B
    		Activator
    WK500B is a potent and orally active BCL6 inhibitor with a KD of 1.61 μM. WK500B engages intracellular BCL6 and disrupts BCL6‑corepressor interactions to reactivate BCL6 target genes. WK500B exerts cytotoxicity against diffuse large B‑cell lymphoma cells and induces apoptosis and cell cycle arrest. WK500B suppresses germinal center formation in C57BL/6 mice and DLBCL tumor growth in SCID xenograft models without observable toxicity. WK500B can be used for the study of diffuse large B‑cell lymphoma (DLBCL).
    WK500B
  • HY-144792
    Bcl-2-IN-7
    		p53 Activator
    Bcl-2-IN-7 (compound 6) is a potent Bcl-2 (B-cell lymphoma-2) inhibitor. Bcl-2-IN-7 down-regulates the expression of Bcl-2, and increases the expression of p53, Bax, and caspase-7 mRNA. Bcl-2-IN-7 induces cell cycle arrest and apoptosis in breast cancer MCF-7 cells. Bcl-2-IN-7 shows good anticancer activity, with IC50 values of 20.17, 22.64, 45.57, and 51.50 μM against MCF-7, LoVo, HepG2, and A549 cell lines, respectively.
    Bcl-2-IN-7
  • HY-P991314
    NMC-001
    		Inhibitor
    NMC-001 is a human IgG1 monoclonal antibody (mAb) targeting MDM2. NMC-001 can be used in pancreatic cancer research. Recommended isotype control: Human IgG1 kappa, Isotype Control (HY-P99001).
    NMC-001
  • HY-N18386
    Altissimacoumarin F
    		p53 Inhibitor
    Altissimacoumarin F (Compound 4) is a terpenylated coumarin. Altissimacoumarin F can be isolated from the stem bark of Ailanthus altissima. Altissimacoumarin F enhances SIRT1 activity, decreases p53 transcriptional activity. Altissimacoumarin F can be used for the research of age-related disorders.
    Altissimacoumarin F
  • HY-169688
    NA-17
    		Activator
    NA-17 is a naphthalimide compound with anti-tumor activity and lower toxicity to normal cells like HL-7702 and WI-38. NA-17 exhibits a p53-dependent selective inhibition in various NSCLC cells, inducing the accumulation of active p53 in the mitochondria and nuclei of NSCLC cells. NA-17 can cause cell cycle arrest in the G1 phase, leading to apoptosis and cell death.
    NA-17
  • HY-W741987
    6,7-Dehydro Norethindrone
    		Activator
    6,7-Dehydro Norethindrone (6,7-Didehydronorethisterone) (Compound 26) is a Norethisterone (HY-B0554) metabolite. 6,7-Dehydro Norethindrone can be produced by the biotransformation of Norethisterone using Rhizopus microsporus PT2906. 6,7-Dehydro Norethindrone induces Apoptosis, binds to p53 and inhibits the degradation of p53. 6,7-Dehydro Norethindrone selectively exhibits antitumor activity against cervical cancer.
    6,7-Dehydro Norethindrone
  • HY-126311
    4-Hydroxyresveratrol
    		Inducer
    4-Hydroxyresveratrol (3,4,5,4'-Tetrahydroxystibene), a Resveratrol (HY-16561) analog, differentially induces pro-apoptotic p53/Bax gene expression. 4-Hydroxyresveratrol induces apoptosis in SV40 virally transformed WI38 cells (WI38VA) cells, but not in WI38 cells. 4-Hydroxyresveratrol significantly induces the expression of p53, GADD45 and Bax genes and concomitantly suppresses the expression of bcl-2 gene in WI38VA.
    4-Hydroxyresveratrol
  • HY-175318S
    p53 Activator 15
    		Activator
    p53 Activator 15 is an orally active p53 Y220C activator. p53 Activator 15 enhances the DNA binding of p53 Y220C (SC50 = 0.58 nM) and significantly inhibits NUGC-3 cell proliferation. p53 Activator 15 effectively inhibits tumor growth in NUGC-3 xenograft mouse and rat models. p53 Activator 15 can be used to study gastric cancer.
    p53 Activator 15
  • HY-180820
    Dimethyl bisphenolate
    		p53 Activator
    Dimethyl bisphenolate (Compound DMB) is a natural neolignan derivative with orally active anti-tumor activity. Dimethyl bisphenolate can inhibit cancer cells proliferation, invasion and migration. Dimethyl bisphenolate can activate the p53 signaling pathway, upregulate the expression of p21 protein, inhibit the activity of the CDK1-cyclin B1 complex, and cause cells to stall at the G2/M phase. Dimethyl bisphenolate can induce ROS production, upregulate pro-apoptotic proteins Noxa and Bim, downregulate anti-apoptotic protein Bcl-2, activate caspase-9 and caspase-3, and ultimately induce cell apoptosis. Dimethyl bisphenolate can be used for research of glioblastoma.
    Dimethyl bisphenolate
  • HY-181048
    CK1α-IN-1
    		p53 Activator
    CK1α-IN-1 (Compound 7a) is a selective CK1α inhibitor with an IC50 of 10.96 nM. CK1α-IN-1 dose-dependently stabilizes p53 protein. CK1α-IN-1 has anticancer activity against acute monocytic leukemia.
    CK1α-IN-1
  • HY-P1755
    p53 (17-26)
    p53 (17-26) is a peptide derived from the P53 MDM2 binding domain, with a Kd of 50 nM for MDM2. p53 (17-26) causes cell lysis by damaging cancer cells and nuclear membranes, and induces cancer cell necrosis. p53 (17-26) exhibits antitumor activity and is applicable to research related to pancreatic cancer.
    p53 (17-26)
Cat. No. Product Name / Synonyms Application Reactivity
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Download MDM-2/p53 Signaling Pathway Map.

p53 is at the centre of biological interactions that translates stress signals into cell cycle arrest or apoptosis. Upstream signaling to p53 increases its level and activates its function as a transcription factor in response to a wide variety of stresses, whereas downstream components execute the appropriate cellular response. 

 

Cell Stress: p53 induction by acute DNA damage begins when DNA double-strand breaks trigger activation of ATM, a kinase that phosphorylates the CHK2 kinase, or when stalled or collapsed DNA replication forks recruit ATR, which phosphorylates CHK1. p53 is a substrate for both the ATM and ATR kinases, as well as for CHK1 and CHK2, which coordinately phosphorylate p53 to promote its stabilization. These phosphorylation events are important for p53 stabilization, as some of the modifications disrupt the interaction between p53 and its negative regulators MDM2 and MDM4. MDM2 and MDM4 bind to the transcriptional activation domains of p53, thereby inhibiting p53 transactivation function, and MDM2 has additional activity as an E3 ubiquitin ligase that causes proteasome-mediated degradation of p53. Phosphorylation also allows the interaction of p53 with transcriptional cofactors, which is ultimately important for activation of target genes and for responses such as cell cycle arrest, DNA repair, apoptosis and senescence. Non-receptor tyrosine kinase c-Abl can also be activated by DNA damage. Then the JNK/p38 is activated and leads to p53 activation[1][2]. 

 

Oncogenic signaling: The response to oncogene activation depends on the binding of ARF to MDM2. ARF is normally expressed at low levels in cells. Inappropriately increased E2F or Myc signals, stemming from oncogene activation, leads to the increased expression of ARF, which inhibits MDM2 by blocking its E3 ubiquitin ligase activity, uncoupling the p53-MDM2 interaction, thereby segregating it from nucleoplasmic p53[3].

 

The PI3K-Akt pathway activates MDM2 and increases the ubiquitination of p53. 

 

Reference:
[1]. Chène P, et al. Inhibiting the p53-MDM2 interaction: an important target for cancer therapy. Nat Rev Cancer. 2003 Feb;3(2):102-9.
[2]. Brown CJ, et al. Awakening guardian angels: drugging the p53 pathway. Nat Rev Cancer. 2009 Dec;9(12):862-73. 
[3]. Polager S, et al. p53 and E2f: partners in life and death. Nat Rev Cancer. 2009 Oct;9(10):738-48. doi: 10.1038/nrc2718.