Related Experiment Videos
Regulation of p53 stability and activity in response to genotoxic stress
M S Colman1, C A Afshari, J C Barrett
1Cancer and Aging Group, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, PO Box 12233, MD C2-15, Research Triangle Park, NC, USA.
Abstract:
The p53 tumor suppressor is a universal sensor of genotoxic stress that regulates the transcription of genes required for cell-cycle arrest and apoptosis. In response to DNA damage, the p53 protein is phosphorylated at its amino-terminus and becomes stabilized upon disruption of an interaction with its negative regulator, MDM2. Subsequent phosphorylation and acetylation of p53 promote different interactions with other proteins and with target gene regulatory elements to facilitate cell-cycle arrest, apoptosis, or adaptation in response to DNA damage. Downstream of p53, p21 is responsible for growth arrest in G1, but other p53 target genes are responsible for G2 cell-cycle arrest. In response to genotoxic insult, p53-induced apoptosis results from overlapping downstream pathways that both suppress mitogenic and survival signaling and promote pro-apoptotic signaling. Adaptation to DNA damage is manifested by p53-mediated expression of its negative regulator, MDM2. The frequency of observed mutations in p53 predicts that its inactivation is a requisite step in tumorigenesis, as p53 is mutated in approximately 50% of human tumors. Thus, it is likely that in the remaining tumors, genetic aberrations will occur in pathways that regulate p53 or in pathways directly downstream of p53. The advances in the understanding of p53 signaling over the past few years point to many potential overlapping signaling pathways, where mutations may occur as alternative modes to p53 mutation.
Insights
The p53 tumor suppressor protein guards against DNA damage by controlling cell-cycle arrest and apoptosis. Mutations in p53 or its regulatory pathways are crucial in nearly half of all human tumors.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- The p53 tumor suppressor is a key sensor of genotoxic stress.
- p53 regulates genes involved in cell-cycle arrest and apoptosis.
- p53 activity is tightly controlled by its negative regulator, MDM2.
Purpose of the Study:
- To elucidate the intricate signaling pathways regulated by p53 in response to DNA damage.
- To understand the role of p53 mutations and pathway dysregulation in tumorigenesis.
- To explore the mechanisms of cell-cycle arrest, apoptosis, and adaptation mediated by p53.
Main Methods:
- Analysis of p53 protein modifications (phosphorylation, acetylation).
- Investigation of p53 interactions with regulatory proteins and DNA.
- Examination of downstream p53 target genes (e.g., p21, MDM2).
- Review of genetic aberrations in p53 and related pathways in human tumors.
Main Results:
- p53 stabilization occurs via MDM2 interaction disruption following DNA damage.
- Post-translational modifications of p53 dictate interactions and downstream effects.
- p53 controls G1 and G2 cell-cycle arrest through distinct target genes.
- p53-mediated apoptosis involves suppression of survival signals and promotion of pro-apoptotic signals.
- Tumorigenesis frequently involves p53 inactivation or alterations in its regulatory network.
Conclusions:
- p53 acts as a central node in DNA damage response pathways.
- Dysregulation of p53 signaling is a critical step in the development of many human cancers.
- Understanding p53 network complexity reveals alternative mutation strategies in tumorigenesis.