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-P10780
    RFRP-3 (mouse)
    		Activator
    RFRP-3 (mouse) is a functional ortholog of avian gonadotropin inhibitory hormone (GnIH), binding to GPR147. RFRP-3 (mouse) reduces Progesterone synthesis by inhibiting FSHR and key enzymes involved in steroidogenesis (P450scc, 3β-HSD, StAR). RFRP-3 (mouse) induces Apoptosis (increase of p53). RFRP-3 (mouse) also suppresses the ERK signaling pathway. RFRP-3 (mouse) can be used for research of follicular development.
    RFRP-3 (mouse)
  • HY-122038
    NU-8165
    NU-8165 is an inhibitor of the MDM2-p53 protein-protein interaction with anti-tumor activity. Optimization of NU-8165 was guided by MDM2 NMR titrations, which indicated key binding interaction regions. NU-8165 activated MDM2 and p21 transcription in cell-based assays and showed modest selectivity for wild-type p53 cell lines.
    NU-8165
  • HY-103640R
    Amifostine thiol (dihydrochloride) (Standard)
    		p53 Activator
    Amifostine thiol (dihydrochloride) (Standard) is the analytical standard of Amifostine thiol (dihydrochloride). This product is intended for research and analytical applications. Amifostine thiol (WR-1065) dihydrochloride can protect normal tissues from the toxic effects of certain cancer agents and activate p53 through a JNK-dependent signaling pathway.
    Amifostine thiol (dihydrochloride) (Standard)
  • HY-159938
    p38α inhibitor 6
    		p53 Activator
    p38α inhibitor 6 (compound 19) is a p38α inhibitor with the IC50 of 0.68 μM. p38α inhibitor 6 induces cell apoptosis and arrests cell cycle at G0 and G2/M phase. p38α inhibitor 6 decreases the TNF-α concentration as well as increased the expression of tumor suppressor gene p53, Bax/BCL-2 ratio and caspase 3/7.
    p38α inhibitor 6
  • HY-18052
    AM-8553
    		Inhibitor
    AM-8553 is a MDM2/p53 inhibitor (KD: 0.4 nM for MDM2). AM-8553 has anti-tumor activity
    AM-8553
  • HY-162432
    MDM2-IN-27
    		Inhibitor
    MDM2-IN-27 targets MDM2 protein (Ki = 0.4 nM). MDM2-IN-27 activates the anti-tumor activity of p53 and induces apoptosis by blocking the negative regulation of p53 by MDM2.
    MDM2-IN-27
  • HY-P10610
    Peptide 234CM
    Peptide 234CM is a peptide containing isoleucine at position 3, corresponding to the sequence of a point mutation in p53 codon 234. Peptide 234CM induces potent cytotoxic T cell (CTL) and antitumor immune responses against mutant p53.
    Peptide 234CM
  • HY-160448
    p53 Activator 9
    		p53 Activator
    p53 Activator 9 (example D-4) is a p53 activator with EC50 of 1.699μM.
    p53 Activator 9
  • HY-W281364
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine is a mutagenic compound.
    2-Ammo-3-memyl-imidazo-[4,5-f]-quinoIine
  • HY-147776
    Antiproliferative agent-8
    		Inhibitor
    Antiproliferative agent-8 (Compound 5a) is an anti-cancer agent. Antiproliferative against-8 has antiproliferative activity. Antiproliferative agent-8 significantly increases the P53 levels.
    Antiproliferative agent-8
  • HY-145900
    S100A2-p53-IN-1
    		Inhibitor
    S100A2-p53-IN-1 (compound 51) is a S100A2-p53 interactions inhibitor. S100A2 is a Ca2+ binding protein with implications in cell signaling and is known to be upregulated in pancreatic cancer. S100A2-p53-IN-1 can inhibit the growth of the MiaPaCa-2 pancreatic cancer cell line (GI50 of 1.2-3.4 μM).
    S100A2-p53-IN-1
  • HY-173309
    P53/TLR2 modulator-1
    		Modulator
    P53/TLR2 modulator-1 (Compound Z9) is a modulator that targets both the P53 pathway and TLR2 simultaneously, exhibiting anti-radiation activity. P53/TLR2 modulator-1 reduces apoptosis by inhibiting the radiation-induced expression of P53 and Bax. At the same time, it activates the TLR2 pathway, upregulates the expression of downstream proteins MyD88 and P65, and promotes the secretion of cytokines such as IL-6, thus exerting an anti-radiation effect. P53/TLR2 modulator-1 shows significant anti-radiation activity against both AHH-1 cells and HUVECs. It can also increase the survival rate of C57BL/6J mice irradiated with a lethal dose of radiation and reduce the damage to their hematopoietic system, the villous structure of the small intestine, and the spleen caused by radiation. P53/TLR2 modulator-1 can be used in the research of radiation injury-related diseases.
    P53/TLR2 modulator-1
  • HY-143241
    HDAC-IN-34
    		p53 Activator
    HDAC-IN-34 (compound 27) is a potent HDAC inhibitor, with IC50 values of 0.022 and 0.45 μM for HDAC1 and HDAC6, respectively. HDAC-IN-34 can bind to DNA and cause DNA damage. HDAC-IN-34 causes cells apoptosis through p53 signaling pathway. HDAC-IN-34 exhibits significant anti-proliferation effect against HCT-116 cells, with an IC50 of 1.41 μM.
    HDAC-IN-34
  • HY-146105
    Anticancer agent 65
    		p53 Activator
    Anticancer agent 65 (compound 4c) shows excellent activity in cancer cell lines, especially A549 cells, with an IC50 of 1.07 μM. Anticancer agent 65 induces S-phase arrest in A549 cells and increases the expression level of p53 and p21. Anticancer agent 65 causes apoptosis, ROS generation and collapse of MMP in A549 cells.
    Anticancer agent 65
  • HY-159175
    XM-U-14
    		Inducer
    XM-U-14 is a selective PROTAC USP7 Degrader (DC50: 0.74 nM in inducing USP7 degradation in RS4;11 cell line). XM-U-14 upregulates the levels of p53 and p21. XM-U-14 also significantly inhibits acute lymphoblastic leukemia (ALL) cell growth (IC50: 0.5 nM and 8.3 nM for RS4;11 cells and Reh cells respectively). XM-U-14 induces apoptosis and cycle arrest. XM-U-14 inhibits tumor growth. (Blue: VHL ligand (HY-159465), Black: linker (HY-W539783); Pink: USP7 inhibitor (HY-159464)).
    XM-U-14
  • HY-P10286
    Phage-derived 12/1 peptide
    		Inhibitor
    Phage-derived 12/1 peptide exhibits antitumor activity by targeting MDM2 and MDMX, an thus disrupt the MDM2-p53 and MDMX-p53 interaction, with IC50 of 0.15 and 1.25 μM.
    Phage-derived 12/1 peptide
  • HY-156919
    p53 Activator 8
    p53 Activator 8 (compound 5) is a p53 activator. p53 Activator 8 has potent anti-proliferative activity against MCF7 breast cancer cell lines with an IC50 value of 0.5 μM.
    p53 Activator 8
  • HY-12734
    AM-8735
    		MDM2 Inhibitor
    AM-8735 is a potent and selective MDM2 inhibitor with an IC50 of 25 nM.
    AM-8735
  • HY-146540
    GEM-5
    		Activator
    GEM-5 is a gemcitabine-based conjugate containing a HIF-1α inhibitor (YC-1) (IC50=30 nM). GEM-5 can significantly down-regulate the expression of HIF-1α and up-regulate the expression of tumor suppressor p53. GEM-5 induces the apoptosis of A2780 cells and inhibits tumor growth.
    GEM-5
  • HY-18331
    MI-219
    		MDM2 Inhibitor
    MI-219 is an antagonist for MDM2 with a Ki of 13.3 μM. MI-219 inhibits the MDM2-p53 interaction, inhibits thus the proliferation of FSCCL cells, with an IC50 of 2.5 μM.
    MI-219
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.