IndraLab

"Small molecule RO-5963 blocks homo- and heterodimerization of MDM2 and MDMX, triggering the activation of p53 signalling pathway and the induction of apoptosis (Graves et al., 2012)."

"This interaction between MDM2 and MDM4 activates the E3 ligase activity of MDM2 and induces proteosomal degradation of p53 to suppress its endogenous cellular levels below the threshold required for transactivation of target genes, such as the cyclin dependent kinase (CDK) inhibitor p21."

"Therefore, in cancer patients receiving anti-PD1, anti-PDL1, or anti-CTLA4 drugs, regular endocrine assessment is recommended to make early diagnosis and appropriate treatment.This study aimed to elucidate whether p53 reactivation by peptide 3 inhibitor of the MDM2/MDM4 heterodimer (14) formation, whose administration is known to inhibit tumor growth, could have beneficial effects on tumor progression by restoring antitumoral immune responses whilst avoiding the development of autoimmune responses.The effect of p53 reactivator on immunotypes in the peripheral blood of patients affected by thyroid carcinoma was investigated."

"Note that in contrast to several studies [41], we did not find Mdm2 stabilization by MdmX and efficient p53 degradation by the Mdm2/MdmX heterodimer."

"The examples include MEL23 and its analogs, a number of MMRi (MDM2-MDMX RING domain inhibitors), and a pyrrolidone derivative that inhibits E3 ligase activity of MDM2/MDMX complex to activate p53 (Herman et al., 2011; Zhuang et al., 2012; Wu et al., 2015)."

"In addition, the interaction between p53 and Mdm2 or MdmX suppresses the transcriptional activities of p53."

"It has been indicated that MDM2 forms a heterodimer or heterooligomer with MDMX through their C-terminal domains to inhibit p53 during early embryogenesis."

"MDMX has emerged as a viable target for cancer therapy, both for its own ability to inhibit p53 and its role in the MDM2/MDMX complex, especially in cancers where amplification of MDMX is more prevalent than MDM2 (Gembarska et al., 2012; Burgess et al., 2016)."

"In addition, the interaction between p53 and Mdm2 or MdmX suppresses the transcriptional activities of p53 [3]."

"An increase in the levels of p53 and phosphorylated p53 could occur as a result of inhibition of the Mdm2-mediated p53 degradation by means of complex formation between Mdm2 and MdmX."

"Additionally, mutation or deletion of the Mdmx RING also prevents Mdm2 and Mdmx interaction and triggers p53 dependent lethality in vivo."

"Although MDM4 alone is unable to target p53 for ubiquitin-proteasome-dependent degradation 6, the MDM2 and MDM4 heterodimer has been shown more potent degrading the p53 protein as compared to the MDM2 homodimer 7, 8."

"It remains to be established in future studies if the three miRNAs are actively excreted from prostate cancer cells to prevent p53 stabilisation and subsequent inhibition of the androgen axis or if MDM4 transcript levels are actively decreased upon androgen stimulation to stabilise AR protein via modulating the stoichiometric ratio of the MDM2/MDM4 heterodimer."