"Indeed, we have already highlighted above that p53 mutants can be stabilized in cells notably via the formation of MDM2-Hsp90-p53 complex leading to MDM2 inhibition."
"Previous studies showed that in tumor cells, chaperone protein HSP90 interacts with mutant p53 to form MDM2-p53-HSP90 complex and consequently stabilizes mutant p53 xref , xref , xref ."
"In particular, in the heterozygous form, many mutant p53 proteins show a dominant-negative effect via heterotetramerization with WT p53, preventing its normal checkpoint functions. xref Second, many p53 mutants acquire gain-of-function oncogenic activities, promoting cell survival, proliferation, invasion, migration, chemoresistance, tissue remodeling, chronic inflammation, as well as inactivation of p53 paralogs p63 and p73, which belong to the same p53 tumor suppressor family and are important tumor suppressors. xref , xref Not surprisingly, tumors depleted of the WT p53 gene retain the mutant form of the protein and thus gain a selective advantage. xref Importantly, although p53 mutations are present in approximately 50% of cancers, in almost all cases where WT p53 is retained, its tumor suppressor function is eliminated via direct binding of two main p53 binding protein groups: (1) cellular mouse double minute 2 homolog (MDM2) or transformed mouse 3T3 cell double minute 4 (MDM4: also known as MDMX), xref , xref or (2) proteins encoded by DNA viruses such as the E6 protein of high-risk human papillomavirus (HPV). xref Finally, mutations in the conformation-sensitive core domain of p53 induce the association of p53 with chaperone proteins such as heat shock protein 90 (Hsp90) forming a complex p53-Hsp90-MDM2 and provoking the MDM2 inhibition leading to the stabilization of p53 mutants. xref "
"As Hsp90 binds to MDM2 and p53, xref , xref and MDM2 binds to p53 and MDMX, xref we determined whether 17AAG could affect these interactions."
"However, to be functional this complex requires an interaction with HDAC6. xref This is why an OV bearing a p53 transgene and a shRNA sequence against HDAC6 could be useful to impair the complex MDM2-Hsp90-p53 formation and promote the degradation of p53 mutants by MDM2 or by other chaperone-associated E3 ubiquitin ligase such as CHIP. xref , xref OV-p53 also could be combined with other molecules capable of blocking the pathways regulated by mutant p53."
"Prior work investigating mutant p53 stability has demonstrated a strong link
to Hsp90-mutant p53 interaction, which has been shown to block MDM2-dependent
ubiquitination in various cancer cell lines ( xref )."