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

Frederik De Smet, Mirian Saiz Rubio, Daphne Hompes, Evelyne Naus, Greet De Baets, Tobias Langenberg, Mark S. Hipp, Bert Houben, Filip Claes, Sarah Charbonneau, Javier Delgado Blanco, Stephane Plaisance, Shakti Ramkissoon, Lori Ramkissoon, Colinda Simons, Piet van den Brandt, Matty Weijenberg, Manon Van Engeland, Sandrina Lambrechts, Frederic AmantAndre D'Hoore, Keith L. Ligon, Xavier Sagaert, Joost Schymkowitz*, Frederic Rousseau*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)
108 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)24-38
Number of pages15
JournalJournal of Pathology
Volume242
Issue number1
DOIs
Publication statusPublished - May 2017

Keywords

  • p53 aggregation
  • proteostasis
  • colon cancer
  • glioblastoma
  • nuclear inclusion bodies
  • UBIQUITIN-PROTEASOME SYSTEM
  • HEAT-SHOCK RESPONSE
  • PROTEIN AGGREGATION
  • NEURODEGENERATIVE DISEASES
  • HUNTINGTONS-DISEASE
  • CELLULAR-MODEL
  • A-BETA
  • GAIN
  • PML
  • MDM2

Cite this