p53-Tumor Suppression

The vast majority of p53-regulated genes are induced in response to various stress signals and are responsible for maintaining genetic stability, DNArepair, regulation of crucial cell-cycle check points, and finally induction of apoptosis. The activity of p53 is tightly controlled by two major negative regulators including murine double minute 2 (MDM2; EC 6.3.2.19) and 4 (MDM4 or MDMX) proteins. Human MDM2 and MDMX are structurally related and contain three well-conserved domains: an N-terminal domain (responsible for p53 binding), a zinc-finger domain (function largely unknown) and a C-terminal RING domain (responsible for formation of homo- and heterodimers). Additionally, the RING domain of MDM2 confers E3 ubiquitin ligase activity. Concentration/activity of p53 is kept at low level in unstressed cells. This is accomplished by three parallel mechanisms mediated by MDM2 and/or MDMX. First, MDM2 and MDMX bind the N-terminal transactivation domain (TAD) of p53, preventing thereby its interaction with the transcription machinery and resulting in the inhibition of p53-responsive gene expression. Second, MDM2/X proteins export p53 outside the nucleus into the cytoplasm where it can no longer activate transcription. Finally, MDM2 marks p53 for proteasomal degradation[1]. Many tumors overproduce MDM2 to impair p53 function. Therefore, restoration of p53 activity by inhibiting the p53–MDM2 binding represents an attractive novel approach to cancer therapy[2].


[1] K. Zak et al. Mdm2 and MdmX inhibitors for the treatment of cancer: a patent review (2011 – present). Exp. Opin. Ther. Pat. 2013, 23, 425-448.
[2] B.T. Vu, L. Vassilev. Small-Molecule Inhibitors of the p53-MDM2 Interaction. Curr. Top. Microbiol. Immun. 2011, 348, 151-172.

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3152 PAWI-2 Inhibitor which targets both Wnt signaling and ATM/p53 €120.00

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