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  Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation

De Smet, F., Rubio, M. S., Hompes, D., Naus, E., De Baets, G., Langenberg, T., et al. (2017). Nuclear inclusion bodies of mutant and wild-type p53 in cancer: a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation. Journal of Pathology: an Official Journal of the Pathological Society, 242(1), 24-38. doi:10.1002/path.4872.

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 Creators:
De Smet, Frederik1, Author
Rubio, Mirian Saiz1, Author
Hompes, Daphne1, Author
Naus, Evelyne1, Author
De Baets, Greet1, Author
Langenberg, Tobias1, Author
Hipp, Mark S.2, Author              
Houben, Bert1, Author
Claes, Filip1, Author
Charbonneau, Sarah1, Author
Blanco, Javier Delgado1, Author
Plaisance, Stephane1, Author
Ramkissoon, Shakti1, Author
Ramkissoon, Lori1, Author
Simons, Colinda1, Author
van den Brandt, Piet1, Author
Weijenberg, Matty1, Author
Van England, Manon1, Author
Lambrechts, Sandrina1, Author
Amant, Frederic1, Author
D'Hoore, Andre1, AuthorLigon, Keith L.1, AuthorSagaert, Xavier1, AuthorSchymkowitz, Joost1, AuthorRousseau, Frederic1, Author more..
Affiliations:
1external, ou_persistent22              
2Hartl, Franz-Ulrich / Cellular Biochemistry, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565152              

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Free keywords: UBIQUITIN-PROTEASOME SYSTEM; HEAT-SHOCK RESPONSE; PROTEIN AGGREGATION; NEURODEGENERATIVE DISEASES; HUNTINGTONS-DISEASE; CELLULAR-MODEL; A-BETA; GAIN; PML; MDM2Oncology; Pathology; p53 aggregation; proteostasis; colon cancer; glioblastoma; nuclear inclusion bodies;
 Abstract: Although p53 protein aggregates have been observed in cancer cell lines and tumour tissue, their impact in cancer remains largely unknown. Here, we extensively screened for p53 aggregation phenotypes in tumour biopsies, and identified nuclear inclusion bodies (nIBs) of transcriptionally inactive mutant or wild-type p53 as the most frequent aggregation-like phenotype across six different cancer types. p53-positive nIBs co-stained with nuclear aggregation markers, and shared molecular hallmarks of nIBs commonly found in neurodegenerative disorders. In cell culture, tumour-associated stress was a strong inducer of p53 aggregation and nIB formation. This was most prominent for mutant p53, but could also be observed in wild-type p53 cell lines, for which nIB formation correlated with the loss of p53's transcriptional activity. Importantly, protein aggregation also fuelled the dysregulation of the proteostasis network in the tumour cell by inducing a hyperactivated, oncogenic heat-shock response, to which tumours are commonly addicted, and by overloading the proteasomal degradation system, an observation that was most pronounced for structurally destabilized mutant p53. Patients showing tumours with p53-positive nIBs suffered from a poor clinical outcome, similar to those with loss of p53 expression, and tumour biopsies showed a differential proteostatic expression profile associated with p53-positive nIBs. p53-positive nIBs therefore highlight a malignant state of the tumour that results from the interplay between (1) the functional inactivation of p53 through mutation and/or aggregation, and (2) microenvironmental stress, a combination that catalyses proteostatic dysregulation. This study highlights several unexpected clinical, biological and therapeutically unexplored parallels between cancer and neurodegeneration. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Language(s): eng - English
 Dates: 2017-03-232017
 Publication Status: Published in print
 Pages: 15
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000399674800005
DOI: 10.1002/path.4872
 Degree: -

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Title: Journal of Pathology : an Official Journal of the Pathological Society
  Other : J. Pathol.
Source Genre: Journal
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Publ. Info: Edinburgh : Longman
Pages: - Volume / Issue: 242 (1) Sequence Number: - Start / End Page: 24 - 38 Identifier: ISSN: 0022-3417
CoNE: https://pure.mpg.de/cone/journals/resource/954927663103_2