Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington's disease

Rachel H. Mansky; Erin A. Greguske; Dahyun Yu; Nicole Zarate; Taylor A. Intihar; Wei Tsai; Taylor G. Brown; Mackenzie N. Thayer; Kompal Kumar; Rocio Gomez-Pastor

doi:10.1016/j.celrep.2023.112198

Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington's disease

Rachel H. Mansky, Erin A. Greguske, Dahyun Yu, Nicole Zarate, Taylor A. Intihar, Wei Tsai, Taylor G. Brown, Mackenzie N. Thayer, Kompal Kumar, Rocio Gomez-Pastor

Neuroscience

Research output: Contribution to journal › Article › peer-review

Abstract

p53 and HSF1 are two major transcription factors involved in cell proliferation and apoptosis, whose dysregulation contributes to cancer and neurodegeneration. Contrary to most cancers, p53 is increased in Huntington's disease (HD) and other neurodegenerative diseases, while HSF1 is decreased. p53 and HSF1 reciprocal regulation has been shown in different contexts, but their connection in neurodegeneration remains understudied. Using cellular and animal models of HD, we show that mutant HTT stabilized p53 by abrogating the interaction between p53 and E3 ligase MDM2. Stabilized p53 promotes protein kinase CK2 alpha prime and E3 ligase FBXW7 transcription, both of which are responsible for HSF1 degradation. Consequently, p53 deletion in striatal neurons of zQ175 HD mice restores HSF1 abundance and decrease HTT aggregation and striatal pathology. Our work shows the mechanism connecting p53 stabilization with HSF1 degradation and pathophysiology in HD and sheds light on the broader molecular differences and commonalities between cancer and neurodegeneration.

Original language	English (US)
Article number	112198
Journal	Cell reports
Volume	42
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2023.112198
State	Published - Mar 28 2023

Bibliographical note

Funding Information:
We are grateful to Drs. Michael Lee and Razaul Karim for sharing their expertise on p53 in PD and AD and for kindly providing p53 fl/fl mice and other resources, Maha Syed and Joyce Meints for technical assistance, and Jason Mitchell for assistance with confocal microscopy. This research was funded by the National Institute of Neurological Disorders and Stroke ( R01NS110694 ) to R.G.P. and the American Cancer Society and Institutional Research Grant ACS#IRG-16-189-59-IRG107 to R.G.P.

Publisher Copyright:
© 2023 The Authors

Keywords

CP: Molecular biology
CP: Neuroscience
HSF1
Huntington's disease
MDM2
p53
striatal pathology

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.112198

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title = "Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington's disease",

abstract = "p53 and HSF1 are two major transcription factors involved in cell proliferation and apoptosis, whose dysregulation contributes to cancer and neurodegeneration. Contrary to most cancers, p53 is increased in Huntington's disease (HD) and other neurodegenerative diseases, while HSF1 is decreased. p53 and HSF1 reciprocal regulation has been shown in different contexts, but their connection in neurodegeneration remains understudied. Using cellular and animal models of HD, we show that mutant HTT stabilized p53 by abrogating the interaction between p53 and E3 ligase MDM2. Stabilized p53 promotes protein kinase CK2 alpha prime and E3 ligase FBXW7 transcription, both of which are responsible for HSF1 degradation. Consequently, p53 deletion in striatal neurons of zQ175 HD mice restores HSF1 abundance and decrease HTT aggregation and striatal pathology. Our work shows the mechanism connecting p53 stabilization with HSF1 degradation and pathophysiology in HD and sheds light on the broader molecular differences and commonalities between cancer and neurodegeneration.",

keywords = "CP: Molecular biology, CP: Neuroscience, HSF1, Huntington's disease, MDM2, p53, striatal pathology",

author = "Mansky, {Rachel H.} and Greguske, {Erin A.} and Dahyun Yu and Nicole Zarate and Intihar, {Taylor A.} and Wei Tsai and Brown, {Taylor G.} and Thayer, {Mackenzie N.} and Kompal Kumar and Rocio Gomez-Pastor",

note = "Funding Information: We are grateful to Drs. Michael Lee and Razaul Karim for sharing their expertise on p53 in PD and AD and for kindly providing p53 fl/fl mice and other resources, Maha Syed and Joyce Meints for technical assistance, and Jason Mitchell for assistance with confocal microscopy. This research was funded by the National Institute of Neurological Disorders and Stroke ( R01NS110694 ) to R.G.P. and the American Cancer Society and Institutional Research Grant ACS#IRG-16-189-59-IRG107 to R.G.P. Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1016/j.celrep.2023.112198",

language = "English (US)",

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AU - Mansky, Rachel H.

AU - Greguske, Erin A.

AU - Yu, Dahyun

AU - Zarate, Nicole

AU - Intihar, Taylor A.

AU - Tsai, Wei

AU - Brown, Taylor G.

AU - Thayer, Mackenzie N.

AU - Kumar, Kompal

AU - Gomez-Pastor, Rocio

N1 - Funding Information: We are grateful to Drs. Michael Lee and Razaul Karim for sharing their expertise on p53 in PD and AD and for kindly providing p53 fl/fl mice and other resources, Maha Syed and Joyce Meints for technical assistance, and Jason Mitchell for assistance with confocal microscopy. This research was funded by the National Institute of Neurological Disorders and Stroke ( R01NS110694 ) to R.G.P. and the American Cancer Society and Institutional Research Grant ACS#IRG-16-189-59-IRG107 to R.G.P. Publisher Copyright: © 2023 The Authors

PY - 2023/3/28

Y1 - 2023/3/28

N2 - p53 and HSF1 are two major transcription factors involved in cell proliferation and apoptosis, whose dysregulation contributes to cancer and neurodegeneration. Contrary to most cancers, p53 is increased in Huntington's disease (HD) and other neurodegenerative diseases, while HSF1 is decreased. p53 and HSF1 reciprocal regulation has been shown in different contexts, but their connection in neurodegeneration remains understudied. Using cellular and animal models of HD, we show that mutant HTT stabilized p53 by abrogating the interaction between p53 and E3 ligase MDM2. Stabilized p53 promotes protein kinase CK2 alpha prime and E3 ligase FBXW7 transcription, both of which are responsible for HSF1 degradation. Consequently, p53 deletion in striatal neurons of zQ175 HD mice restores HSF1 abundance and decrease HTT aggregation and striatal pathology. Our work shows the mechanism connecting p53 stabilization with HSF1 degradation and pathophysiology in HD and sheds light on the broader molecular differences and commonalities between cancer and neurodegeneration.

AB - p53 and HSF1 are two major transcription factors involved in cell proliferation and apoptosis, whose dysregulation contributes to cancer and neurodegeneration. Contrary to most cancers, p53 is increased in Huntington's disease (HD) and other neurodegenerative diseases, while HSF1 is decreased. p53 and HSF1 reciprocal regulation has been shown in different contexts, but their connection in neurodegeneration remains understudied. Using cellular and animal models of HD, we show that mutant HTT stabilized p53 by abrogating the interaction between p53 and E3 ligase MDM2. Stabilized p53 promotes protein kinase CK2 alpha prime and E3 ligase FBXW7 transcription, both of which are responsible for HSF1 degradation. Consequently, p53 deletion in striatal neurons of zQ175 HD mice restores HSF1 abundance and decrease HTT aggregation and striatal pathology. Our work shows the mechanism connecting p53 stabilization with HSF1 degradation and pathophysiology in HD and sheds light on the broader molecular differences and commonalities between cancer and neurodegeneration.

KW - CP: Molecular biology

KW - CP: Neuroscience

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KW - MDM2

KW - p53

KW - striatal pathology

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Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington's disease

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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