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-15954C
    (R)-NVP-CGM097
    		Inhibitor
    (R)-NVP-CGM097 is the R-enantiomer of NVP-CGM097 (HY-15954). NVP-CGM097 is a potent and selective MDM2 inhibitor with an IC50 of 1.7 nM for hMDM2.
    (R)-NVP-CGM097
  • HY-N12281
    Sennoside
    		Inducer
    Sennoside is an orally active apoptosis inducer and stimulant laxative, found in Senna (Cassia angustifolia). Sennoside induces overexpression of wild-type p53 and p21/WAF as part of pathways mediating colonic epithelial cell apoptosis. Sennoside stimulates colonic peristalsis, reverses net water, sodium, chloride absorption to secretion and enhances potassium and calcium secretion. Sennoside increases paracellular permeability to small molecules, accelerates colon transit and softens fecal pellets. Sennoside can be used for the research of constipation, melanosis coli, and colorectal cancer.
    Sennoside
  • HY-174299
    SIRT1-IN-6
    SIRT1-IN-6 (Compound NP1) is a SIRT1 inhibitor (IC50: 9.7 μM). SIRT1-IN-6 increases p53 acetylation. SIRT1-IN-6 can be used for research of prophylaxis and neurodegenerative diseases or cancer.
    SIRT1-IN-6
  • HY-15035R
    S-Diclofenac (Standard)
    		Activator
    S-Diclofenac (Standard) is the analytical standard of S-Diclofenac. This product is intended for research and analytical applications. S-Diclofenac (ACS 15) is a hybrid molecule of an H2S donor and the NSAID diclofenac. S-Diclofenac activates the p53 signaling pathway, and inhibits the activation of JNK. S-Diclofenac exhibits antioxidant and anti-inflammatory activities.
    S-Diclofenac (Standard)
  • HY-N18301
    Americanin A
    		Activator
    Americanin A is a Neolignan. Americanin A can be isolated from the seeds of Phytolacca americana. Americanin A activates ATM and ATR, initiating the subsequent signal transduction cascades that include Chk1, Chk2, and tumor suppressor p53. Americanin A targets selectively Skp2 for degradation and thereby stabilizes p27. Americanin A suppresses the activity of Cyclin B1 and its partner cdc2 to prevent entry into Mitosis. Americanin A induces Apoptosis by producing excessive ROS. Americanin A has anti-cancer activity against colorectal cancer.
    Americanin A
  • HY-101266R
    Milademetan (Standard)
    		MDM2 Inhibitor
    Milademetan (Standard) is the analytical standard of Milademetan (HY-101266). This product is intended for research and analytical applications. Milademetan (DS-3032) is a specific and orally active MDM2 inhibitor for the research of acute myeloid leukemia (AML) or solid tumors. Milademetan (DS-3032) induces G1 cell cycle arrest, senescence and apoptosis.
    Milademetan (Standard)
  • HY-N8210R
    Homoeriodictyol (Standard)
    		Antagonist
    Homoeriodictyol (Standard) is the analytical standard of Homoeriodictyol (HY-N8210). This product is intended for research and analytical applications. Homoeriodictyol is an orally active, bitter-tasting flavanone that can penetrate the blood-brain barrier. Homoeriodictyol enhances synaptic-related protein expression through NCOA4-mediated ferritin autophagy. Homoeriodictyol improves memory impairment in mice by inhibiting the NLRP3 inflammasome. Homoeriodictyol protects human endothelial cells from oxidative damage by activating Nrf2 and inhibiting mitochondrial dysfunction. Homoeriodictyol enhances ROS activity and induces apoptosis, exhibiting anticancer effects. Homoeriodictyol inhibits the survival and migration of androgen-resistant prostate cancer cells in vitro. Homoeriodictyol exerts antinociceptive activity in mice in vivo.
    Homoeriodictyol (Standard)
  • HY-119666
    Rooperol
    Rooperol is a norlignan analog with antitumor, anti-inflammatory, and antioxidant activities. Rooperol induces apoptosis in CSCs through a mitochondrial-induced increase in ROS and a p53-dependent pathway, while also downregulating the expression of key stem cell regulatory factors, such as Oct4, Nanog, and Sox2, ultimately exerting its anticancer effects.
    Rooperol
  • HY-108638R
    NSC 146109 hydrochloride (Standard)
    		p53 Activator
    NSC 146109 hydrochloride (Standard) is the analytical standard of NSC 146109 (hydrochloride) (HY-108638). This product is intended for research and analytical applications. NSC 146109 hydrochloride is a small-molecule p53 activator that target MDMX and can be used for breast cancer research. NSC 146109 hydrochloride is a pseudourea derivative, promotes breast cancer cells to undergo apoptosis through activating p53 and inducing expression of proapoptotic genes.
    NSC 146109 hydrochloride (Standard)
  • HY-W016181
    Phenylhydroquinone
    		p53 Activator 99.21%
    Phenylhydroquinone (PHQ) is an orally active thymic atrophy inducer which can up-regulate apoptosis through activation of p53. PHQ can be used for research of thymic atrophy.
    Phenylhydroquinone
  • HY-100354S
    C16-Ceramide-13C16
    C16-Ceramide-13C16 is a 13C-labeled C16-Ceramide (HY-100354).
    C16-Ceramide-<sup>13</sup>C<sub>16</sub>
  • HY-W747601
    Chlorphoxim
    		Activator
    Chlorphoxim is a broad-spectrum and highly efficient insecticide. Chlorphoxim kills pests by inhibiting AChE. Chlorphoxim inhibits the activities of SOD and CAT in zebrafish embryos. Chlorphoxim induces oxidative stress in zebrafish embryos by activating ROS. Chlorphoxim induces apoptosis by upregulating the expression levels of Bax, Bcl2 and p53 in zebrafish embryos. Chlorphoxim exhibits neurotoxicity and developmental toxicity. Chlorphoxim is used in agricultural research for the control of various pests.
    Chlorphoxim
  • HY-112903A
    YW3-56 hydrochloride
    		Activator
    YW3-56 (hydrochloride) is a PAD inhibitor. YW3-56 (hydrochloride) activates p53 target genes. YW3-56 (hydrochloride) activates ATF and blocks autophagy flux. YW3-56 induces ER stress through the PERK-eIF2α-ATF4 signaling cascade and inhibits the mTOR signaling. YW3-56 (hydrochloride) inhibits triple-negative breast cancer.
    YW3-56 hydrochloride
  • HY-N2993R
    Polyporenic acid C (Standard)
    		Activator
    Polyporenic acid C (Standard) is an analytical standard of Polyporenic acid C (HY-N2993). This product is intended for research and analytical applications. Polyporenic acid C is a lanostane-type triterpenoid. Polyporenic acid C can be isolated from Poria cocos. Polyporenic acid C causes the cleavage of caspase-8 and caspase-3, as well as the cleavage of PARP. Polyporenic acid C reduces the phosphorylation level of Akt (Ser473), increases the phosphorylation of PTEN and p53 (Ser15), and activates JNK. Polyporenic acid C induces Apoptosis. Polyporenic acid C shows anticancer activity against non-small cell lung cancer.
    Polyporenic acid C (Standard)
  • HY-N2037AR
    Higenamine hydrochloride (Standard)
    		Activator
    Higenamine (hydrochloride) (Standard) is the analytical standard of Higenamine (hydrochloride). This product is intended for research and analytical applications. Higenamine hydrochloride is a selective LSD1 inhibitor (IC50=1.47 μM) that can be isolated from aconite. Higenamine hydrochloride has anti-inflammatory and antibacterial activity. Higenamine (Norcoclaurine) can attenuate IL-1β-induced Apoptosis through ROS-mediated PI3K/Akt signaling pathway. Higenamine hydrochloride protects brain cells from oxygen deprivation. Higenamine can promote bone formation in osteoporosis through the SMAD2/3 pathway. Higenamine hydrochloride can be used to study cancer, inflammation, cardiorenal syndrome and other diseases.
    Higenamine hydrochloride (Standard)
  • HY-W715812
    Bromuconazole
    		Activator
    Bromuconazole is a triazole fungicide with oral efficacy and blood-brain barrier permeability. Bromuconazole protects crops from various fungal contaminations. Bromuconazole exhibits cytotoxicity against a variety of cancer cells, induces G0/G1 cell cycle arrest and inhibits DNA synthesis in cancer cells, and triggers cytoskeletal structural disorder, genotoxic damage, apoptotic (apoptosis) cell death, and mitochondrial membrane depolarization. Bromuconazole activates caspase-3, induces excessive production of ROS, p53 and Bax, lipid peroxidation, increased activities of SOD and CAT, and downregulates Bcl-2. By upregulating p-ERK1/2 and p-JNK, Bromuconazole disrupts the MAPK signaling pathway, impairs the cellular stress response of human trophoblast cells and endometrial cells, and damages the implantation process. Bromuconazole is applicable to research related to glioma, colon cancer, reproductive injury (implantation dysfunction), and cardiac dysfunction.
    Bromuconazole
  • HY-121893
    p53-MDM2-IN-3
    		Inhibitor
    p53-MDM2-IN-3 (Compound 5s) is an orally active p53-MDM2 inhibitor with a Ki value of 0.25 μM. p53-MDM2-IN-3 exerts antitumor activity by inhibiting NF-κB pathway.
    p53-MDM2-IN-3
  • HY-N12768
    Rhodojaponin VI
    		Inhibitor
    Rhodojaponin VI is an orally active diterpenoid compound found in hododendron molle G. Don
    (Ericaceae) (RM). Rhodojaponin VI binds rat N-Ethylmaleimide-sensitive fusion (NSF) with a Kd of 1.03 μM. Rhodojaponin VI blocks the MDM2-Notch1 signalling pathway by reducing MDM2 and Notch1 expression. Rhodojaponin VI indirectly reduces Cav2.2 current intensity by inhibiting NSF-mediated Cav2.2 trafficking. Rhodojaponin VI alleviates glomerulonephritis progression and podocyte injury in passive heymann nephritis rats. Rhodojaponin VI also has antinociceptive effects. Rhodojaponin VI can be used for the researches of heymann nephritis and pain.
    Rhodojaponin VI
  • HY-101666R
    HBX 41108 (Standard)
    HBX 41108 (Standard) is the analytical standard of HBX 41108 (HY-101666). This product is intended for research and analytical applications. HBX 41108 is an inhibitor of ubiquitin-specific protease 7 (USP7) with an IC50 of 424 nM. HBX 41108 inhibits USP7-mediated p53 deubiquitination to stabilize p53 and inhibits cancer cell growth. BX 41108 can be used in cancer and diabetes research.
    HBX 41108 (Standard)
  • HY-107566A
    Conessine dihydrobromide
    		Inhibitor
    Conessine dihydrobromide is an orally active and BBB-penetrable selective histamine H3 receptor antagonist. The pKi values of Conessine dihydrobromide for rat and human H3 receptors are 7.61 and 8.27, respectively. Conessine dihydrobromide is an inhibitor of the multidrug efflux pump system in Pseudomonas aeruginosa and can enhance the activity of antibiotics. Conessine dihydrobromide has antimalarial activity. Conessine dihydrobromide can also be used in the research of muscle atrophy.
    Conessine dihydrobromide
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.