TY - JOUR
T1 - Nuclear inclusion bodies of mutant and wild-type p53 in cancer
T2 - a hallmark of p53 inactivation and proteostasis remodelling by p53 aggregation
AU - De Smet, Frederik
AU - Rubio, Mirian Saiz
AU - Hompes, Daphne
AU - Naus, Evelyne
AU - De Baets, Greet
AU - Langenberg, Tobias
AU - Hipp, Mark S.
AU - Houben, Bert
AU - Claes, Filip
AU - Charbonneau, Sarah
AU - Blanco, Javier Delgado
AU - Plaisance, Stephane
AU - Ramkissoon, Shakti
AU - Ramkissoon, Lori
AU - Simons, Colinda
AU - van den Brandt, Piet
AU - Weijenberg, Matty
AU - Van Engeland, Manon
AU - Lambrechts, Sandrina
AU - Amant, Frederic
AU - D'Hoore, Andre
AU - Ligon, Keith L.
AU - Sagaert, Xavier
AU - Schymkowitz, Joost
AU - Rousseau, Frederic
PY - 2017/5
Y1 - 2017/5
N2 - 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.
AB - 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.
KW - p53 aggregation
KW - proteostasis
KW - colon cancer
KW - glioblastoma
KW - nuclear inclusion bodies
KW - UBIQUITIN-PROTEASOME SYSTEM
KW - HEAT-SHOCK RESPONSE
KW - PROTEIN AGGREGATION
KW - NEURODEGENERATIVE DISEASES
KW - HUNTINGTONS-DISEASE
KW - CELLULAR-MODEL
KW - A-BETA
KW - GAIN
KW - PML
KW - MDM2
U2 - 10.1002/path.4872
DO - 10.1002/path.4872
M3 - Article
C2 - 28035683
SN - 0022-3417
VL - 242
SP - 24
EP - 38
JO - Journal of Pathology
JF - Journal of Pathology
IS - 1
ER -