Distinct target genes and effector processes appear to be critical for p53-activated responses to acute DNA damage versus p53-mediated tumour suppression

By

Valent, Liz
Strasser, Andreas

Type

Article

Date of Publication

2013-6-30

Original Publication

Biodiscovery

Volume

8

Series / Issue

Issue: 8

Pages

1--16

Subjects

apoptosis , cell cycle arrest , DNA damage , Noxa , p21 , p53 , puma , senescence , tumour suppression

Contributed by

Pensoft Publishers

Language

English

Published by

Newport on Tay Scottish Science Press

Identifiers

DOI: https://doi.org/10.7750/BioDiscovery.2013.8.3

 

Abstract

The p53 tumour suppressor is the most frequently mutated gene in human cancer. This transcription factor can be activated by diverse cellular stresses, including DNA damage and oncogene activation. Through transcriptional induction of appropriate target genes, p53 can stimulate activity in a broad range of effector pathways, most notably cell cycle arrest, cellular senescence and apoptotic cell death. Insensitivity to cell death-inducing signals and deregulated proliferation are two key hallmarks of cancer cells. Given that p53 inhibits proliferation and induces apoptosis, it was widely believed that these processes are the most critical ones for p53-mediated tumour suppression. However, this dogma has been challenged. In striking contrast to p53-deficient mice, which all develop tumours before 250 days of age, mutant mice in which expression of the p53 target genes that are critical for induction of cell cycle arrest and apoptosis is impaired or abrogated are not cancer-prone. This demonstrates that distinct effector processes are critical for the p53-mediated acute response to DNA damage versus p53-mediated tumour suppression. The discovery that cell cycle arrest, senescence and apoptosis are not essential for p53-mediated tumour suppression re-launches the search for the p53 target genes and effector processes that are critical to prevent tumour development, with coordination of DNA repair being a leading contender.