The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies.

The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Research Abstract Details 

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The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Abstract Text:

The transcriptional regulator p53 plays an essential role in tumor suppression. Accordingly, it is found mutated, and its activity is reduced, in many human cancers. Recent reports show that some cancers are characterized by a loss of function of wild-type p53, which, in several cases, accumulates in intracellular aggregates. Although the nature of such aggregates is still unclear, recent evidence indicates that the p53 C-terminal and core domains can undergo amyloid aggregation in vitro under mild denaturing conditions, although no information is available on the largely unstructured N-terminal transactivation domain. We therefore decided to investigate the amyloid propensity of the acidic unfolded 1-63 fragment of the transactivation domain, cloned, expressed, and purified from a bacterial strain. Here we show that, when exposed to acidic pH, the 1-63 fragment forms thioflavine T-positive aggregates whose amyloid nature was confirmed by Fourier transform infrared spectroscopy analysis, atomic force microscopy, and x-ray diffraction. These aggregates were shown to be cytotoxic to human SH-SY5Y cells by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction, lactate dehydrogenase release, and caspase-3 activity assays. These results add new significant details to the picture describing the propensity of single domains of p53 to aggregate, further suggesting that, under suitable destabilizing conditions, the whole protein may aggregate into amyloid assemblies in vivo.

The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Publishing Authors By Initials

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The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Biophysical journal

VOLUME: 94

Page Numbers: 3635-46

Journal Abbreviation: Biophys. J.

ISSN: 1542-0086

DAY: 16

MONTH: 01

YEAR: 2008

The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies. Information

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LANGUAGE: eng

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Grant and Affiliation Information for The (1-63) region of the p53 transactivation domain aggregates in vitro into cytotoxic amyloid assemblies.

AFFILIATION: Department of Biochemical Sciences, University of Florence, 50134 Florence, Italy. stefania.rigacci@unifi.it <stefania.rigacci@unifi.it>

Country: United States

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MEDLINETA: Biophys J

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