Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers

Martinho, May San; Nancarrow, Derek J.; Lawrence, Theodore S.; Beer, David G.; Ray, Dipankar

doi:10.1016/j.jcmgh.2020.10.012

Cited by 8 publications

(6 citation statements)

References 105 publications

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“…In cancer cells, molecular chaperones increase the stability and protect the oncogenic p53 mutants from proteasomal degradation 12,[60][61][62] . This results in accumulation of high cellular levels of mutant p53, crucial for its oncogenic gain of function (GOF) activities 16,17,61,63 .…”

Section: Dnaja2 Stabilizes the Oncogenic Conformation Of P53 Mutants ...mentioning

confidence: 99%

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

Zoltsman,

Dang,

Kuchersky

et al. 2023

Preprint

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SUMMARYJ-domain proteins (JDPs) constitute a large family of molecular chaperones that bind a broad spectrum of substrates, targeting them to Hsp70, thus determining the specificity and activating the entire chaperone functional cycle. The malfunction of JDPs is therefore inextricably linked to myriad human disorders. Here we uncover a novel mechanism by which chaperones recognize misfolded clients, present in class-A JDPs. Through a newly-identified β-hairpin site, these chaperones detect changes in protein dynamics at the initial stages of misfolding, prior to exposure of hydrophobic regions or large structural rearrangements. The JDPs then sequester misfolding-prone proteins into large oligomeric assemblies, protecting them from aggregation. Through this mechanism, class-A JDPs bind destabilized p53 mutants, preventing clearance of these oncoproteins by Hsp70-mediated degradation, thus promoting cancer progression. Removal of the β-hairpin abrogates this protective activity while minimally affecting other chaperoning functions. This suggests the class-A JDP β-hairpin as a highly specific target for cancer therapeutics.

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Section: Dnaja2 Stabilizes the Oncogenic Conformation Of P53 Mutants ...mentioning

confidence: 99%

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

Zoltsman,

Dang,

Kuchersky

et al. 2023

Preprint

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“…These findings demonstrate the importance of analyzing regions outside exons 5–8 and suggest that mutations of TP53 in exon 4 may also play a role in EAC development. To the best of our knowledge, all of the point mutations identified in our study were previously described in EAC [ 10 – 13 , 15 , 17 , 19 , 20 , 43 ], with the exception of S127P, P128H (both in patient 83), Q136* (patient 51), T211I (patient 81) and Y220C (patient 62). Codon 220 has been reported as a “hotspot” for TP53 mutations in other types of cancers [ 42 ].…”

Section: Discussionmentioning

confidence: 98%

Targeted genetic and epigenetic profiling of esophageal adenocarcinomas and non-dysplastic Barrett’s esophagus

et al. 2022

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Background Despite the efforts to describe the molecular landscape of esophageal adenocarcinoma (EAC) and its precursor lesion Barrett’s esophagus (BE), discrepant findings are reported. Here, we investigated the prevalence of selected genetic (TP53 mutations and microsatellite instability (MSI) status) and epigenetic (DNA promoter hypermethylation of APC, CDKN2A, MGMT, TIMP3 and MLH1) modifications in a series of 19 non-dysplastic BE and 145 EAC samples. Additional biopsies from adjacent normal tissue were also evaluated. State-of-the-art methodologies and well-defined scoring criteria were applied in all molecular analyses. Results Overall, we confirmed frequent TP53 mutations among EAC (28%) in contrast to BE, which harbored no mutations. We demonstrated that MSI and MLH1 promoter hypermethylation are rare events, both in EAC and in BE. Our findings further support that APC, CDKN2A, MGMT and TIMP3 promoter hypermethylation is frequently seen in both lesions (21–89%), as well as in a subset of adjacent normal samples (up to 12%). Conclusions Our study further enlightens the molecular background of BE and EAC. To the best of our knowledge, this is one of the largest studies addressing a targeted analysis of genetic and epigenetic modifications simultaneously across a combined series of non-dysplastic BE and EAC samples.

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“…They reported a refinement in cognitive and motor activity [133]. The action of Statins revealed depends on the types of TP53 mutations [134]. Statins could be inducing the degradation of misfolding and mutant TP53 by increasing CHIP C terminus of Hsc70-interaction proteins, which moderates the exporting TP53 from nuclear and degradation of TP53 via the ubiquitin-proteasome mechanism [135].…”

Section: Discussionmentioning

confidence: 99%

Role of statins in regulating molecular pathways following traumatic brain injury: A system pharmacology study

Mahmoudi

Heydari

Markina

et al. 2022

Biomedicine & Pharmacotherapy

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Chaperones and Ubiquitin Ligases Balance Mutant p53 Protein Stability in Esophageal and Other Digestive Cancers

Cited by 8 publications

References 105 publications

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

A unique chaperoning mechanism in Class A JDPs recognizes and stabilizes mutant p53

Targeted genetic and epigenetic profiling of esophageal adenocarcinomas and non-dysplastic Barrett’s esophagus

Role of statins in regulating molecular pathways following traumatic brain injury: A system pharmacology study

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