Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242706 (hyperoxia)
 5,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The HAP1 protein (also known as APE/Ref-1) is a bifunctional human nuclear enzyme required for repair of apurinic/apyrimidinic sites in DNA and reactivation of oxidized proto-oncogene products. To gain insight into the biological roles of HAP1, the effect of expressing antisense HAP1 RNA in HeLa cells was determined. The constructs for antisense RNA expression consisted of either a full-length HAP1 cDNA or a genomic DNA fragment cloned downstream of the CMV promoter in pcDNAneo. Stable HeLa cell transfectants expressing HAP1 antisense RNA were found to express greatly reduced levels of the HAP1 protein compared to equivalent sense orientation and vector-only control transfectants. The antisense HAP1 transfectants exhibited a normal growth rate, cell morphology and plating efficiency, but were hypersensitive to killing by a wide range of DNA damaging agents, including methyl methanesulphonate, hydrogen peroxide, menadione, and paraquat. However, survival after UV irradiation was unchanged. The antisense transfectants were strikingly sensitive to changes in oxygen tension, exhibiting increased killing compared to controls following exposure to both hypoxia (1% oxygen) and hyperoxia (100% oxygen). Consistent with a requirement for HAP1 in protection against hypoxic stress, expression of the HAP1 protein was found to be induced in a time-dependent manner in human cells during growth under 1% oxygen. The possible involvement of a depletion of cellular glutathione being linked to the hypoxic stress-sensitive phenotype of the antisense HAP1 transfectants came from the finding that they also exhibited hypersensitivity to buthionine sulphoximine, an inhibitor of glutathione biosynthesis. We conclude that the HAP1 protein is a key factor in cellular protection against a wide variety of cellular stresses, including DNA damage and a change in oxygen tension.
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PMID:A role for the human DNA repair enzyme HAP1 in cellular protection against DNA damaging agents and hypoxic stress. 780 Apr 76

Chronic oxidative stress has been hypothesized to be a major contributor to the aging process. The continued exposure to reactive oxygen species (ROS) generated by oxidative metabolism or environmental sources can damage critical cellular structures and be responsible for some age-related pathology. The exposure of rodents to 100% oxygen, isobaric hyperoxia, increases ambient ROS levels and significantly increases apoptosis in brain. The deleterious effects of ROS also include increased lipid peroxidation, protein oxidation, and DNA damage. Although differences in the relative amounts of oxidative stress in young and old brains have been observed, the mechanisms responsible for impaired aging-associated DNA repair processes have not been characterized. We measured DNA levels of the DNA repair enzyme apurinic/apyrimidinic endonuclease (APE/Ref-1) protein by Western blot analysis in the brains of young (3-month) and old (30-month) male rats exposed to isobaric hyperoxia. Given that APE/Ref-1 is the rate-limiting enzyme in the repair pathway of apurinic/apyrimidinic sites generated in DNA by oxidative damage, we assumed that APE/Ref-1 protein levels were a good reflection of ongoing DNA base excision repair. Isobaric hyperoxia stimulated APE/Ref-1 expression in the hippocampus and basal forebrain of young rats experiencing 100% oxygen for 6 hr, while aged rats showed no significant changes in APE/Ref-1 protein levels in all brain areas at any time tested (0-48 hr) after hyperoxia. Differences in the stress-induced levels of expression of DNA repair enzymes may contribute to apoptotic increases and pathology associated with the aging process.
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PMID:APE/Ref-1 responses to oxidative stress in aged rats. 984 54

Exposure to chronic oxidative stress during elevated oxygen (hyperoxia) damages DNA and inhibits cell proliferation in G(1) through induction of the cyclin-dependent kinase inhibitor p21. Cells that fail to express p21 growth-arrest in S phase. The observation that growth arrest in G(1) is associated with reduced DNA damage and enhanced survival suggests that p21 may affect expression of base excision repair (BER) enzymes used to repair oxidized DNA. This hypothesis was tested in p21 wild-type and p21-deficient mice and human lung adenocarcinoma H1299 cells with tetracycline-on regulated expression of p21. The mRNA levels of Ogg1, Tdg, Udg, Mpg, Nth1, and Mgmt remained constant during 3 days of hyperoxia. The expression of Ogg1, Nth1, and APE protein also remained unchanged. Although hyperoxia increased p21, its absence did not significantly affect expression of these repair enzymes. These findings reveal that hyperoxia induces p21 without significantly altering BER enzyme expression. This suggests that p21 may protect oxidized cells by affecting the activity of BER enzymes and/or through other mechanisms, such as apoptosis.
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PMID:p21(Cip1/WAF1/Sdi1) does not affect expression of base excision DNA repair enzymes during chronic oxidative stress. 1589 18