Chapter 9: p53 and Apoptosis
prevents the proliferation of damaged cells.
Enforces cell-cycle checkpoints
Initiates DNA repair pathway if damage is detected
Promotes apoptosis if damage is severe
Cell damage initiates a kinase cascade stress signal, activating p53 (transcription
factor), which enters the nucleus and promotes target genes including the CDKI
P53 activity is lost in greater than 50% of cancers by somatic mutation or deletion
P53 -/- mice are born normal, but most develop lymphomas within 6
P53 can be signaled by a lack of nucleotides, UV radiation, ionizing radiation, oncogene
signaling, hypoxia, or blockage of transcription.
P53 will then promote cell-cycle arrest, DNA repair, block of angiogenesis, or
In a resting, unstressed cell, p53 is actively transcribed but maintained at low levels.
is a p53 specific ubiquitin ligase that is actually one of p53’s target genes
In response to stress, p53 is rapidly phosphorylated (by stress kinases
), no longer
being destroyed by mdm2-mediated proteasomal degradation.
Phosphorylation of p53 changes the shape of it’s amino terminal
, which is it’s mdm2-
The marjority of p53 mutations are missense mutations
which are substitutions of one
amino-acid for another.
They are usually clustered in the DNA-binding domain, inactivating p53.
A mutation at codon 175 creates a structural mutant
, disabling p53 from
A mutation at codons 248 or 273 create a contact mutant
, which is a
mutation at the point where p53 makes direct contact with the double
P53’s Structural Domains:
- Binds to specific elements within regulatory regions of
- Recruits transcription factors and accessory proteins to
form activating or inhibiting complexes
Telomerization (oligo) Domain
- p53 functions as a tetramer (4 proteins)
A mutation in one p53 allele can produce a phenotype, even in the presence of a wt allele.
P53 is a dominant-negative
This is because it functions as a tetramer, and inactivation of one of the 4 proteins
that make it up would cause a phenotype.
Oncogenic signaling upregulates the transcription factor E2F
, which induces the ARF
ARF protein interferes with mdm2, leading to stabilization of p53 and either
arrest or apoptosis.