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Live or let die: the cell's response to p53

Key Points

  • p53 is a tumour-suppressor protein that induces apoptotic cell death in response to oncogenic stress. Malignant progression is dependent on loss of p53 function, either through mutation in the TP53 gene (which encodes p53) itself or by defects in the signalling pathways that are upstream or downstream of p53.

  • Mutations in TP53 occur in about half of all human cancers, almost always resulting in the expression of a mutant p53 protein that has acquired transforming activity.

  • p53-induced apoptosis depends on the ability of p53 to activate gene expression, although transcriptionally independent activities of p53 can also contribute to the apoptotic response.

  • The apoptotic and cell-cycle arrest activities of p53 can be separated, and apoptotic cofactors that play a specific role in allowing p53-induced death are being identified.

  • Regulation of the apoptotic function of p53 is associated with selective activation of apoptotic target genes. Cofactors that specifically contribute to p53-mediated activation of apoptotic target genes include JMY, ASPP and the other p53-family members p63 and p73.

  • Phosphorylation of p53 regulates its ability to activate the expression of apoptotic target genes, and other post-translational modifications such as acetylation might also have a role.

  • In tumours that retain wild-type p53, the apoptotic response might be hindered by defects in the apoptotic cofactors. These, therefore, represent additional targets for the design of therapeutics that are aimed at reactivating p53-mediated apoptosis in cancer cells.

Abstract

Compared with many normal tissues, cancer cells are highly sensitized to apoptotic signals, and survive only because they have acquired lesions — such as loss of p53 — that prevent or impede cell death. We are now beginning to understand the complex mechanisms that regulate whether or not a cell dies in response to p53 — insights that will ultimately contribute to the development of therapeutic strategies to repair the apoptotic p53 response in cancers.

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Figure 1: The p53 response.
Figure 2: Loss of p53 activity in cancers.
Figure 3: p53 structure and location of tumour-associated mutations.
Figure 4: Several apoptotic pathways are activated by p53.
Figure 5: Model for the regulation of the choice of response to p53.

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Acknowledgements

We apologize to all our colleagues whose excellent papers we have been unable to cite. Also, we thank the members of both the Vousden and Lu laboratories for stimulating discussion and suggestions.

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Correspondence to Karen H. Vousden.

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DATABASES

Cancer.gov

breast cancer

colon cancer

LocusLink

AKT

APAF1

APC

ARF

ASPP1

ASPP2

ATM

BAX

BLM

caspase-8

caspase-9

CBP

CDKN1A

CHK2

cyclin A

cyclin G

E2F1

FAS

HB-EGF

HIPK2

JMY

LKB1

MAPK

MDM2

MDMX

MYC

NF-κB

p300

p53

p53AIP1

p53DINP1

p63

p73

PI3K

PIK3CA

PML

PTEN

PUMA

RAS

RB

SIN3A

SMAC

TNF

TRAIL

TRUNDD

WIP1

WISP1

WNT

XPB

XPD

Glossary

DOMINANT-NEGATIVE MUTANT

A non-functional mutant protein that competes with the normal, non-mutated protein, thereby blocking its activity.

UBIQUITIN LIGASES

A family of enzymes that function in the final step of conjugation of ubiquitin chains to lysine residues in target proteins. Polyubiquitylated proteins are recognized and degraded by the proteasome.

APC

(Adenomatous polyposis coli). A tumour-suppressor gene that is mutated in sporadic colorectal cancers.

DIFFERENTIAL DISPLAY

An expression analysis method in which cDNAs from different samples are amplified by polymerase chain reaction using a combination of random primers and anchored oligo-dT primers.

SAGE

Serial analysis of gene expression that is based on the capture and analysis of a short nucleotide sequence (or tag) that is close to the 3′ end of each cDNA in the sample.

MICROARRAYS

Chips that contain arrays of oligonucleotides that correspond to known genes and that are used to analyse gene expression by hybridization with samples. In contrast to differential display and SAGE, this technique is limited to the analysis of genes that are represented on the chip.

HUMAN PAPILLOMAVIRUS E7

A viral oncoprotein that is derived from certain human papillomavirus types that are associated with an increased risk of cervical cancer. E7 binds and inactivates retinoblastoma.

PEUTZ–JEGHER SYNDROME

A cancer-susceptibility syndrome that is associated with inheritance of mutation in LKB1, a serine/threonine kinase.

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Vousden, K., Lu, X. Live or let die: the cell's response to p53. Nat Rev Cancer 2, 594–604 (2002). https://doi.org/10.1038/nrc864

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