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

Research output: Contribution to journalArticlepeer-review


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 languageEnglish (US)
Article number112198
JournalCell reports
Issue number3
StatePublished - 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


  • 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


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