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Cited by 106Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerProtein Kinase Regulation and GTPase Signaling

A Nuclear Phosphoinositide Kinase Complex Regulates P53

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Choi, Suyong, Chen, Mo, Cryns, Vincent L., Anderson, Richard A.·2019·Nature Cell Biology
DOI 10.1038/s41556-019-0297-2PMC PMC7017954
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Abstract

The tumour suppressor p53 (encoded by TP53) protects the genome against cellular stress and is frequently mutated in cancer. Mutant p53 acquires gain-of-function oncogenic activities that are dependent on its enhanced stability. However, the mechanisms by which nuclear p53 is stabilized are poorly understood. Here, we demonstrate that the stability of stress-induced wild-type and mutant p53 is regulated by the type I phosphatidylinositol phosphate kinase (PIPKI-α (also known as PIP5K1A)) and its product phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2). Nuclear PIPKI-α binds to p53 upon stress, resulting in the production and association of PtdIns(4,5)P 2 with p53. PtdIns(4,5)P 2 binding promotes the interaction between p53 and the small heat shock proteins HSP27 (also known as HSPB1) and αB-crystallin (also known as HSPB5), which stabilize nuclear p53. Moreover, inhibition of PIPKI-α or PtdIns(4,5)P 2 association results in p53 destabilization. Our results point to a previously unrecognized role of nuclear phosphoinositide signalling in regulating p53 stability and implicate this pathway as a promising therapeutic target in cancer.

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  • Under genotoxic stress, IPMK-generated nuclear PIP3 binds to p53, which activates nuclear AKT signaling and suppresses apoptosis.

    “While years of research have primarily investigated AKT signaling at the cell membrane, recent works by Chen et al. [71] and Choi et al. [61] have revealed that, under genotoxic stress, IPMK-generated nuclear PIP3 binds to p53, which activates nuclear AKT signaling and suppresses apoptosis.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [61]

    The Discussion describes a different mechanism under genotoxic stress: PIPKIα generates PI4,5P2, which binds p53 and recruits small heat shock proteins that stabilize it. The Results likewise identify nuclear PI4,5P2—not IPMK-generated PIP3—as the lipid associated with p53. The cited paper does not describe this interaction as activating nuclear AKT signaling or suppressing apoptosis. Page numbers are unavailable in our copy. (LLM, conf=0.88)

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  • IPMK loss does not affect RAD51 transcription, but impairs the mRNA's cytoplasmic export and translation, reducing RAD51 protein production.

    “While IPMK loss does not affect RAD51 transcription, it impairs the mRNA’s cytoplasmic export and translation, ultimately reducing RAD51 protein production.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [61]

    The Results section on PIPKIα and p53 stability reports that PIPKIα deletion reduced mutant p53 protein while leaving p53 mRNA levels unaffected; no page number is available in our copy. Searches for IPMK, RAD51, mRNA export, and translation found no passage addressing the claimed RAD51 mechanism. (LLM, conf=0.76)

    Experimental — accuracy not yet measured

  • PIP3 recognizes a specific sequence in RAD51 transcripts, facilitating their nuclear export through the ALY factor.

    “PIP3 recognizes a specific sequence in RAD51 transcripts, facilitating their nuclear export through the ALY factor.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [61]

    The Results section on p53 association with PI4,5P2 describes lipid binding to p53, not recognition of a sequence in RAD51 transcripts. Searches for RAD51, ALY, and transcript export found no passage in our copy addressing the claimed mechanism. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

  • IPMK-generated PIP3 in mammalian cells regulates nuclear export of RAD51 mRNA.

    “A separate investigation by Wickramasinge et al. [61] discovered that IPMK-generated PIP3 in mammalian cells plays a crucial role in regulating the nuclear export of RAD51 mRNA, a key protein in DNA repair.”

    From From Obscurity to Prominence: IPMK’s Expanding Role in Cellular Signaling, Physiology, and Disease (2025) · cites this paper as [61]

    The Results section on PIPKIα and the Discussion describe PIPKIα-generated PI4,5P2 regulating nuclear p53 stability, not IPMK-generated PIP3 regulating mRNA export. Searches for RAD51 mRNA, IPMK, and Wickramasinghe found no passage in our copy addressing the attributed finding. Page numbers were not available. (LLM, conf=0.76)

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Cited by

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Authors
Choi, S., Chen, M., Cryns, V. L., & Anderson, R. A.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Anderson, Richard A.
ORCID
Venue
Nature Cell Biology
Publisher
Springer Science and Business Media LLC
Published
2019-03-18
Volume
21
Issue
4
Pages
462-475
ISSN
  • 1465-7392 (ISSN-L)
  • 1476-4679
DOI
10.1038/s41556-019-0297-2
PMC
PMC7017954
OpenAlex
W2921628574
Cited by
106
References
4
Citations by year
2026: 10 · 2025: 25 · 2024: 13 · 2023: 6 · 2022: 14 · 2021: 14 · 2020: 12 · 2019: 12
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Cell Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Cancer Research Institute
  • Moffitt Cancer Center
  • National Institutes of Health
  • National Institute of General Medical Sciences (R01GM114386, R35GM134955)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
p53, phosphatidylinositol 4,5-bisphosphate, phosphoinositide signaling, p53 stabilization, mutant p53, HSP27, alphaB-crystallin, small heat shock proteins, tumour suppressor, stress response, cancer therapy targets
MeSH terms
Cell Line, Cell Nucleus, Humans, Tumor Suppressor Protein p53, Phosphotransferases (Alcohol Group Acceptor), Phosphatidylinositol 4,5-Diphosphate, Heat-Shock Proteins, Small, Protein Stability

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