ReviewThe p53 response to DNA damage
Section snippets
The p53 pathway
The p53 tumour suppressor protein plays a pivotal role in the cellular response to a range of environmental and intracellular stresses including agents which cause DNA strand breaks, ultraviolet radiation, hyper-proliferation and hypoxia (for reviews see [1], [2], [3], [4]). p53 acts as a node or hub for incoming stress signals which are then transduced, mainly through the ability of p53 to act as a transcription factor that binds to specific sites in the regulatory regions of p53-responsive
The p53-MDM2 feedback loop
Under normal circumstances, p53 is tightly regulated through its interaction with MDM2, a negative regulatory partner. MDM2 is an E3 ubiquitin ligase which, together with the p300 “transcriptional co-activator” protein (acting as an E4 polyubiquitin ligase), mediates both the ubiquitylation and proteasome-dependent degradation of p53 [2]. The binding of MDM2 to the transactivation domain within the N-terminus of p53 plays an additional role of blocking the interaction of p53 with the
The p53 response following DNA strand breaks
Of the various cellular stresses that initiate a p53 response, the molecular mechanisms by which p53 is activated following DNA double strand breaks are perhaps the most comprehensively understood. Activation of p53 by DNA damage occurs at two levels: the stabilisation of the p53 protein, leading to its accumulation in the nucleus, and activation of biochemical functions encompassed within the p53 protein.
Stabilisation of p53 occurs through inhibition of its degradation by MDM2 and is mediated
Growth arrest or apoptosis?
Different types of cells often show different biological responses to a given stress [1]. For example, thymocytes and splenocytes undergo p53-dependent apoptosis in vivo in response to low levels of ionising radiation. In contrast, fibroblasts arrest in a p53-dependent manner following DNA damage but will nevertheless undergo p53-dependent apoptosis following a different type of stress such as oncogenic transformation. These different cell types may therefore exhibit low and high thresholds,
Concluding remarks
Induction of p53 can occur in response to a range of genotoxic or non-genotoxic stresses leading to the biological outcomes of growth arrest or apoptosis. It is now clear that there is a large and complex range of factors that contribute to the choice between these two general outcomes including the cell type, the type and intensity of initiating stress, p53 levels, the presence of p53 co-activators or regulators and the p53-MDM2 regulatory feedback loop which is itself the major target of
References (45)
- et al.
The p53-Mdm2 module and the ubiquitin system
Semin. Cancer Biol.
(2003) - et al.
Design of a synthetic Mdm2-binding mini protein that activates the p53 response in vivo
Curr. Biol.
(1997) - et al.
A small synthetic peptide, which inhibits the p53-hdm2 interaction, stimulates the p53 pathway in tumour cell lines
J. Mol. Biol.
(2000) - et al.
Study of the cytotoxic effect of a peptide inhibitor of the p53-Hdm2 interaction in tumour cells
FEBS Lett.
(2002) - et al.
Direct interactions between HIF-1 alpha and Mdm2 modulate p53 function
J. Biol. Chem.
(2003) - et al.
Phosphorylation site interdependence of human p53 post-translational modifications in response to stress
J. Biol. Chem.
(2003) - et al.
Acetylation of p53 inhibits its ubiquitination by Mdm2
J. Biol. Chem.
(2002) - et al.
p53AIP1, a potential mediator of p53-dependent apoptosis, and its regulation by Ser-46-phosphorylated p53
Cell
(2000) - et al.
A novel cofactor for p300 that regulates the p53 response
Mol. Cell
(1999) - et al.
ASPP proteins specifically stimulate the apoptotic function of p53
Mol. Cell
(2001)
p53 functions through stress- and promoter-specific recruitment of transcription initiation components before and after DNA damage
Mol. Cell
p53DINP1, a p53-inducible gene, regulates p53-dependent apoptosis
Mol. Cell
PTEN protects p53 from Mdm2 and sensitizes cancer cells to chemotherapy
J. Biol. Chem.
Akt enhances Mdm2-mediated ubiquitination and degradation of p53
J. Biol. Chem.
RB regulates the stability and the apoptotic function of p53 via MDM2
Mol. Cell
Negative regulation of the mammalian UV response by Myc through association with Miz-1
Mol. Cell
The role of p53 in determining sensitivity to radiotherapy
Nat. Rev. Cancer
Live or let die: the cell’s response to p53
Nat. Rev. Cancer
The evolution of diverse biological responses to DNA damage: insights from yeast and p53
Nat. Cell Biol.
The p53-mdm-2 autoregulatory feedback loop
Genes Dev.
The loss of mdm2 induces p53-mediated apoptosis
Oncogene
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Nature
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