# Vogelstein, Lane and Levine 2000: surfing the p53 network

Source: https://onco.cc/key-papers/paper-vogelstein-surfing-p53-network-nature-2000/  
OnCo record `paper-vogelstein-surfing-p53-network-nature-2000` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A concise map of the p53 system as a network: the stresses that activate it, the many genes it controls, and the feedback loops that keep it in check, explaining why a single gene sits at the centre of so much of cancer biology.

## Summary

Written by three of the field's founders, this review presented p53 as a signalling network rather than a single switch. Upstream, DNA damage, oncogene activation, hypoxia and nucleotide depletion converge on p53 through kinases and the MDM2 and ARF regulators; downstream, p53 activates genes for cell cycle arrest, apoptosis, DNA repair and inhibition of angiogenesis. The authors emphasised the MDM2 negative feedback loop, the effects of viral oncoproteins and the fact that most cancers disable the network at one point or another, whether by mutating p53 itself or by altering its regulators.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: Nature
- Year: 2000
- DOI: 10.1038/35042675
- Authors: Vogelstein B, Lane D, Levine AJ.
- Findings: p53 integrates signals from DNA damage, oncogene activation and hypoxia through MDM2, ARF and stress kinases.; Its outputs include cell cycle arrest, apoptosis, DNA repair and anti-angiogenic genes.; Most cancers disable the network, either by TP53 mutation or by altering upstream regulators such as MDM2 amplification or ARF loss.
- What it means: This paper is the reason TP53 status, MDM2 amplification and CDKN2A loss are read together in tumour genomes. It frames the current drug development around MDM2 inhibitors and mutant p53 reactivators as attempts to restore a network rather than a single protein.
- Caveats: A review from 2000; many network components and p53 isoforms were identified later.; Concise by design, so it omits much mechanistic detail.

## Sources

- Full text (DOI): https://doi.org/10.1038/35042675

## Connected records

- key papers: [Hollstein 1991: p53 mutations in human cancers](https://onco.cc/key-papers/paper-hollstein-p53-mutations-science-1991/), [Levine 1997: p53, the cellular gatekeeper for growth and division](https://onco.cc/key-papers/paper-levine-p53-gatekeeper-cell-1997/)
- targets: [MDM2](https://onco.cc/targets/mdm2/), [TP53](https://onco.cc/targets/tp53/)
- institutions: [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/)
- pathways: [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [The p53 network (guardian of the genome)](https://onco.cc/pathways/p53-mdm2-axis/)
- terms: [TP53-mutated (p53-abnormal)](https://onco.cc/terms/tp53-mutated/), [Tumour suppressor gene](https://onco.cc/terms/tumour-suppressor-gene/)
- people: [Bert Vogelstein](https://onco.cc/people/bert-vogelstein/)
- ideas: [A synthetic lethality map for every cancer driver in every tissue context](https://onco.cc/ideas/idea-moon-synthetic-lethality-map-every-driver/), [An open degrader consortium against every undruggable driver transcription factor](https://onco.cc/ideas/idea-moon-open-degrader-consortium/), [Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface](https://onco.cc/ideas/idea-bio1-pmhc-bispecifics-public-drivers/), [Detect tumours changing cell type from RNA in the blood](https://onco.cc/ideas/idea-bio1-cfrna-plasticity-tracking/), [Engineered immune surveillance: long-lived programmed immune cells that patrol for early cancer](https://onco.cc/ideas/idea-moon-engineered-immune-surveillance/), [Extend p53 reactivation beyond the Y220C mutation](https://onco.cc/ideas/idea-bio1-p53-mutant-reactivator-expansion/), [Intercept cancer at the field stage](https://onco.cc/ideas/idea-field-interception/), [Is aneuploidy itself a druggable vulnerability?](https://onco.cc/ideas/idea-targeting-aneuploidy/), [Which patients' blood clones will become leukaemia after treatment?](https://onco.cc/ideas/idea-chip-risk-modifiers/), [Whole-body MRI plus blood DNA surveillance for people with Li-Fraumeni syndrome](https://onco.cc/ideas/idea-prev-li-fraumeni-mri-plus-cfdna/)

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