The p53 pathway: positive and negative feedback loops

The p53 pathway responds to stresses that can disrupt the
fidelity of DNA replication and cell division. A stress
signal is transmitted to the p53 protein by post-translational
modifications. This results in the activation of the
p53 protein as a transcription factor that initiates a
program of cell cycle arrest, cellular senescence or
apoptosis. The transcriptional network of p53-responsive
genes produces proteins that interact with a large number
of other signal transduction pathways in the cell and a
number of positive and negative autoregulatory feedback
loops act upon the p53 response. There are at least seven
negative and three positive feedback loops described here,
and of these, six act through the MDM-2 protein to
regulate p53 activity. The p53 circuit communicates with
the Wnt-beta-catenin, IGF-1-AKT, Rb-E2F, p38 MAP
kinase, cyclin-cdk, p14/19 ARF pathways and the cyclin
G-PP2A, and p73 gene products. There are at least three
different ubiquitin ligases that can regulate p53 in an
autoregulatory manner: MDM-2, Cop-1 and Pirh-2. The
meaning of this redundancy and the relative activity of
each of these feedback loops in different cell types or
stages of development remains to be elucidated. The
interconnections between signal transduction pathways
will play a central role in our understanding of cancer.

Oncogene (2005) 24, 2899–2908