Related Experiment Videos
Hypoxia links ATR and p53 through replication arrest.
Ester M Hammond1, Nicholas C Denko, Mary Jo Dorie
1Center for Clinical Sciences Research, Department of Radiation Oncology, Stanford University, Stanford, CA 94303-5152, USA.
Molecular and Cellular Biology
|February 28, 2002
Summary
Hypoxia triggers p53 protein accumulation via ATR kinase, not DNA damage. This ATR-signaling pathway is crucial for cell cycle arrest during tumor development under low-oxygen conditions.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Phosphorylation of human p53 on serine 15 stabilizes it after DNA damage, mediated by ATM kinases.
- Hypoxia differs from ionizing radiation; it doesn't induce DNA lesions and has distinct p53 accumulation patterns compared to HIF-1.
Purpose of the Study:
- To investigate the mechanism of p53 protein accumulation under hypoxic conditions.
- To determine the role of ATR kinase in hypoxia-induced p53 modification and cell cycle arrest.
Main Methods:
- Analyzing p53 protein accumulation and phosphorylation on serine 15 in cells under severe hypoxia.
- Inhibiting ATR kinase activity to assess its effect on hypoxia-induced p53 changes.
- Correlating p53 accumulation with cell cycle phase and replication status.
Main Results:
- Under severe hypoxia, p53 protein accumulates specifically in S phase, correlating with replication arrest.
- Inhibition of ATR kinase significantly reduces hypoxia-induced p53 phosphorylation on serine 15 and its overall accumulation.
- Hypoxia-induced cell growth arrest is dependent on an ATR-signaling pathway.
Conclusions:
- The ATR kinase is essential for p53 modification and accumulation in response to hypoxia-induced replication stress.
- ATR-dependent signaling plays a critical role in tumor development under hypoxic conditions.
- Hypoxic environments may select for cells with impaired ATR-dependent checkpoint control mechanisms.