Kinetic mechanism of p53 oncogenic mutant aggregation and its inhibition

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Kinetic mechanism of p53 oncogenic mutant aggregation and its inhibition.

Aggregation of destabilized mutants of the tumor suppressor p53 is a major route for its loss of activity. In order to assay drugs that inhibit aggregation of p53, we established the basic kinetics of aggregation of its core domain, using the mutant Y220C that has a mutation-induced, druggable cavity. Aggregation monitored by light scattering followed lag kinetics. Electron microscopy revealed ...

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Targeting Oncogenic Mutant p53 for Cancer Therapy

Among genetic alterations in human cancers, mutations in the tumor suppressor p53 gene are the most common, occurring in over 50% of human cancers. The majority of p53 mutations are missense mutations and result in the accumulation of dysfunctional p53 protein in tumors. These mutants frequently have oncogenic gain-of-function activities and exacerbate malignant properties of cancer cells, such...

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Analysis of mutant p53 for MAR-DNA binding: determining the dominant-oncogenic function of mutant p53

At least some mutant p53 proteins not s imply have los t the wild-type p53 specific tumor suppressor function, but exhibit oncogenic functions on their own. Recently we showed that binding of mutant p53 to MAR/SAR elements is an act ivity specif ic for mutant p53 and clearly distinguishable from the previously reported DNA-binding activities of p53. Since MAR/SAR elements are considered to be i...

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Mutant p53 – Heat Shock Response Oncogenic Cooperation: A New Mechanism of Cancer Cell Survival

The main tumor suppressor function of p53 as a "guardian of the genome" is to respond to cellular stress by transcriptional activation of apoptosis, growth arrest, or senescence in damaged cells. Not surprisingly, mutations in the p53 gene are the most frequent genetic alteration in human cancers. Importantly, mutant p53 (mutp53) proteins not only lose their wild-type tumor suppressor activity ...

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ژورنال

عنوان ژورنال: Proceedings of the National Academy of Sciences

سال: 2012

ISSN: 0027-8424,1091-6490

DOI: 10.1073/pnas.1211550109