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-16942
    Damulin B
    		Inducer
    Damulin B is a dammarane-type saponin found in Gynostemma pentaphyllum. Damulin B can inhibit cancer cell apoptosis, decrease mitochondrial membrane potential, inhibit ROS production and cause G0/G1 phase arrest. Damulin B can prevent Cisplatin (HY-17394)-induced acute kidney injury and induce hair growth. Damulin B shows anti-inflammation anti-diabetic and anti-obesity effect. Damulin B can be used for the researches of cancer, inflammation, metabolic disease, such as lung cancer, osteoarthritis and diabetes.
    Damulin B
  • HY-P5910
    Azurin p28 peptide
    		99.40%
    Azurin p28 peptide is a tumor-penetrated antitumor peptide. Azurin p28 peptide redues proteasomal degradation of p53 through formation of a p28: p53 complex. Azurin p28 peptide induces apoptosis or cell cycle arrest. Azurin p28 peptide inhibits p53-positive tumor growths. Azurin p28 peptide shows antiangiogenic effect by inhibiting phosphorylation of VEGFR-2, FAK and Akt.
    Azurin p28 peptide
  • HY-132595
    Teprasiran
    		p53 Inhibitor
    Teprasiran (QPI-1002) is a small interfering RNA that temporarily inhibits p53-mediated cell death that underlies acute kidney injury (AKI).
    Teprasiran
  • HY-151883
    APE1-IN-2
    		p53 Activator 98.28%
    APE1-IN-2 (compound AP1) is a Pt(IV) proagent, targeting a critical BER protein, apurinic/apyrimidinic endonuclease 1 (APE1). APE1-IN-2 shows anticancer activity. APE1-IN-2 induces intracellular accumulation of platinum and activates DNA damage response and apoptosis signals.
    APE1-IN-2
  • HY-P11056
    REF1 peptide
    		Modulator 99.95%
    REF1 peptide is a PORK1 agonist with an EC50 of 0.028 nM in tomato. REF1 peptide binds to the extracellular domain of PORK1, triggers receptor autophosphorylation, and drives downstream MPK3/MPK6 activation, thereby initiating defense and regeneration signaling cascades. REF1 peptide induces callus formation, inhibits shoot regeneration upon continuous exposure, and enhances the regeneration and transformation efficiency of recalcitrant dicotyledonous and monocotyledonous crops.
    REF1 peptide
  • HY-120122
    PK7088
    		99.11%
    PK7088 is a pyrazole and a specific peptide. PK7088 supports the reactivation of mutant p53 by converting it to a form exhibiting wild-type properties. PK7088 exhibit anticancer activity in cancer research.
    PK7088
  • HY-N0429
    Diosbulbin B
    		p53 Activator 99.90%
    Diosbulbin B, a diterpene lactone, is an anticancer agent. Diosbulbin B is an orally active component of Dioscorea. bulbifera L. Diosbulbin B can inhibit cell proliferation, induce G0/G1 phase arrest and apoptosis. Diosbulbin B can induce autophagy and mitochondrial dysfunction. Diosbulbin B can induce liver injury. Diosbulbin B can be used for the research of cancer, such as non-small cell lung cancer (NSCLC).
    Diosbulbin B
  • HY-110315
    Ischemin sodium
    		Inhibitor 99.32%
    Ischemin sodium is a CBP bromodomain inhibitor that inhibits p53 interaction with CBP and transcriptional activity in cells. Ischemin sodium salt inhibits p53-induced p21 activation with an IC50 value of 5 µM. Ischemin sodium salt also prevents apoptosis in ischemic cardiomyocytes. Ischemin sodium salt can be used in the study of cardiovascular diseases (such as myocardial ischemia).
    Ischemin sodium
  • HY-70027A
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride
    		MDM2 Inhibitor 99.56%
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride is an inhibitor of the interaction between p53 and MDM2 proteins.
    p53 and MDM2 proteins-interaction-inhibitor dihydrochloride
  • HY-B2035
    Pretilachlor
    		Activator 99.25%
    Pretilachlor is a chloroacetamide herbicide with biological activities including endocrine disruption, oxidative stress induction, apoptosis induction, and immunotoxicity. Pretilachlor exerts its effects by interfering with hormone metabolism, inducing oxidative stress, activating apoptotic pathways, and inhibiting immune functions. Pretilachlor upregulates the transcription of P53, Mdm2, and Bbc3, and increases the activities of Caspase3 and Caspase9; it upregulates the transcription of genes in the HPG/HPT axis and the activity of aromatase; it induces oxidative stress, elevates ROS levels, and upregulates CAT, SOD, and GPX. Pretilachlor downregulates the transcription of CXCL-C1C, IL-1β, and IL-8. Pretilachlor disrupts the normal physiological processes and embryonic development of fish, exhibiting significant toxicity. Pretilachlor can be used in studies related to weeding, environmental pollution, and behavioral toxicity in fish.
    Pretilachlor
  • HY-U00441
    DPBQ
    		p53 Activator 99.46%
    DPBQ activates p53 and triggers apoptosis in a polyploid-specific manner, but does not inhibit topoisomerase or bind DNA. DPBQ elicits expression and phosphorylation of p53 and this effect is specific to tetraploid cells.
    DPBQ
  • HY-B0860S
    Diuron-d6
    		Activator 99.50%
    Diuron-d6 is the deuterium labeled Diuron (HY-B0860). Diuron is an orally active phenylurea herbicide. Diuron inhibits photosynthesis in plants by blocking the formation of ATP and NADH. Diuron increases the production of ROS. Diuron increases expression of p53 in certain cell lines. Diuron has herbicidal activity against annual and perennial broadleaf weeds and grass weeds. Diuron promotes DMBA/BBN-induced bladder cancer. Diuron can be used in breast cancer research.
    Diuron-d<sub>6</sub>
  • HY-111550
    Bragsin2
    		Inhibitor 99.85%
    Bragsin2 is a potent, selective and noncompetitive nucleotide exchange factor BRAG2 inhibitor, with an IC50 of 3 μM. Bragsin2 binds at the interface between the PH domain of BRAG2 and the lipid bilayer, leads BRAG2 unable to activate lipidated Arf GTPase. Bragsin2 affects breast cancer stem cells.
    Bragsin2
  • HY-101266B
    Milademetan tosylate hydrate
    		MDM2 Inhibitor 98.89%
    Milademetan (DS-3032) tosylate hydrate is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) tosylate hydrate induces G1 cell cycle arrest, senescence and apoptosis.
    Milademetan tosylate hydrate
  • HY-119979
    Cardanol monoene
    		99.51%
    Cardanol monoene (Cardanol C15:1) is a phenolic compound which can be found in cashew nut shell liquid. Cardanol monoene can inhibit cancer cells proliferation, migration, cause S phase arrest, induce apoptosis, ROS production and mitochondrial depolarization. Cardanol monoene downregulates MMP-2, MMP-9, cyclinA1 expression, regulates CDK2, p53, Bax, cytochrome c, cleaved caspase-3, cleaved PARP, Apaf-1 expression and Bax/Bcl-2 ratio. Cardanol monoene shows weak DPPH radical scavenging activity and AChE inhibition activity. Cardanol monoene is lethal to Artemia salina nauplii. Cardanol monoene. Cardanol monoene can be used for the research of cancer, infection and inflamation.
    Cardanol monoene
  • HY-158968
    MMs02943764
    		Modulator 98.0%
    MMs02943764 is a 1,2,4-triazole derivative with anticancer activity. MMs02943764 has significant antiproliferative effects on multiple cancer cell lines. PAC, a structural analog of MMs02943764, has significant cytotoxicity against the leukemia cell line K562 (IC50=35.264 μM), reduces the degradation of p53 by inhibiting Mdm2 and Pirh2, and induces K562 cell cycle arrest.
    MMs02943764
  • HY-P0121B
    ReACp53 scrambled peptide TFA
    		Control 99.94%
    ReACp53 scrambled peptide TFA is a negative control for ReACp53 (HY-P0121). ReACp53 scrambled peptide can be used in the study of ovarian cancer.
    ReACp53 scrambled peptide TFA
  • HY-171272
    PRDX1-IN-3
    		Activator 99.52%
    PRDX1-IN-3 (compound 19-048) is a PRDX1 covalent inhibitor with anti-colorectal cancer activity. PRDX1-IN-3 can effectively inhibit the proliferation of colorectal cancer cells, and its antitumor effect on nude mice with colorectal cancer carrying PRDX1 gene knockout is significantly reduced. PRDX1-IN-3 also upregulates the downstream genes of the p53 signaling pathway to exert an anticancer effect.
    PRDX1-IN-3
  • HY-19339
    Tenovin-3
    		p53 Activator 98.0%
    Tenovin-3 is a p53 activator.
    Tenovin-3
  • HY-124072
    HL001
    		Modulator 98.90%
    HL001 is an orally active small molecule inhibitor of Cyclophilin A (CypA) and a receptor antagonist of Lysophosphatidic acid 1 (LPA1). HL001 induces cell cycle arrest and apoptosis of tumor cells by p53. HL001 stabilizes p53 by down-regulating G3BP1, inducing reactive oxygen species and DNA damage. HL001 disrupts the interaction between MDM2 and p53-72R in a CypA dependent manner. HL001 has antitumor activity. HL001 can also be used to study pulmonary fibrosis.
    HL001
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.