Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: UMLS:C1658953 (
tumor vasculature
)
2,390
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
The transient opening and closing of
tumor vasculature
result in periods of severe oxygen deprivation (hypoxia) followed by reoxygenation. This exerts a positive selective pressure for cells that have lost their sensitivity to killing by reduced oxygen levels. These cells are effectively resistant to hypoxia-induced apoptosis and conventional therapeutic approaches. Here we show hypoxia-induced S-phase arrest results in regions of single-stranded DNA in stalled replication forks and signals the activation of
ATR
. S-phase cells represent the most sensitive phase of the cell cycle to the stress of hypoxia/reoxygenation. Loss of
ATR
or inhibition of
ATR
kinase activity results in a further loss of reproductive viability in S-phase cells when exposed to hypoxic conditions followed by reoxygenation but has little effect on the inhibition of DNA synthesis. This is, at least in part, mediated via Chk1 signaling because loss of Chk1 also results in increased sensitivity to hypoxia/reoxygenation. The observed decrease in reproductive survival is in part because of the accumulation of DNA damage in S-phase cells during hypoxia exposure in the absence of full
ATR
activity. Therefore,
ATR
acts to protect stalled replication forks during hypoxia exposure. In conclusion,
ATR
and Chk1 play critical roles in the cellular response to hypoxia/reoxygenation, and inhibitors of
ATR
and Chk1 represent new hypoxic cell cytotoxins.
...
PMID:Inhibition of ATR leads to increased sensitivity to hypoxia/reoxygenation. 1537 68
