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)

Previous studies have shown that hyperoxia inhibits proliferation and increases the expression of the tumor suppressor p53 and its downstream target, the cyclin-dependent kinase inhibitor p21(CIP1/WAF1), which inhibits proliferation in the G1 phase of the cell cycle. To determine whether growth arrest was mediated through activation of the p21-dependent G1 checkpoint, the kinetics of cell cycle movement during exposure to 95% O2 were assessed in the Mv1Lu and A549 pulmonary adenocarcinoma cell lines. Cell counts, 5-bromo-2'-deoxyuridine incorporation, and cell cycle analyses revealed that growth arrest of both cell lines occurred in S phase, with A549 cells also showing evidence of a G1 arrest. Hyperoxia increased p21 in A549 but not in Mv1Lu cells, consistent with the activation of the p21-dependent G1 checkpoint. The ability of p21 to exert the G1 arrest was confirmed by showing that hyperoxia inhibited proliferation of HCT 116 colon carcinoma cells predominantly in G1, whereas an isogenic line lacking p21 arrested in S phase. The cell cycle arrest in S phase appears to be a p21-independent process caused by a gradual reduction in the rate of DNA strand elongation. Our data reveal that hyperoxia inhibits proliferation in G1 and S phase and demonstrate that p53 and p21 retain their ability to affect G1 checkpoint control during exposure to elevated O2 levels.
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PMID:The role of p21(CIP1/WAF1) in growth of epithelial cells exposed to hyperoxia. 1123 1

The beneficial effects of supplemental oxygen delivered to patients suffering from acute respiratory distress is offset by its reduction to genotoxic reactive oxygen species (ROS) that inhibit proliferation and kill pulmonary cells. Cells respond to oxygen-induced damage by expressing the tumor suppressor p53 and the cyclin-dependent kinase inhibitor p21(Cip1/WAF1/Sdi1) (p21), which limits proliferation by blocking entry into S phase. Since preventing DNA synthesis during genotoxic stress may enhance survival, the current study examines whether hyperoxia induces p21 through a p53-dependent pathway and whether p21 protects cells from the toxic effects of oxygen. HCT116 colon carcinoma cells and clonal lines lacking p53 or p21were used in this study because they allow direct cytotoxic comparisons between isogenic cells, without complications arising from unknown genetic differences between nonhomologous cell lines. Hyperoxia (95% O2, 5% CO2) increased p53 abundance, phosphorylation of p53 on serine 15, and p21 mRNA and protein in parental HCT116 cells that ceased proliferation. In contrast, p21 was not detected in either p53- or p21-deficient HCT116 cells, which exited the G1 compartment and were arrested in S and G2/M phases during hyperoxia. Trypan blue-dye exclusion revealed that induction of p21 markedly enhanced survival during exposure and colony survival assays showed that p21 enhanced the ability to resume proliferation during recovery in room air. The observation that p53-dependent induction of p21 prevents exit from G1 and promotes survival during hyperoxia is consistent with the importance of limiting DNA replication during genotoxic stress caused by oxygen exposure.
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PMID:p53-dependent induction of p21(Cip1/WAF1/Sdi1) protects against oxygen-induced toxicity. 1156 65

p21(Cip1/WAF1/Sdi1) is a major transcriptional target of p53 that promotes survival of cells exposed to continuous oxidative stress caused by hyperoxia. Because p21 can protect against genotoxic stress by reducing p53-dependent transcription of the proapoptotic proteins PUMA and Bax, the current study uses genetically modified lines of HCT116 colon carcinoma cells to investigate whether p21-mediated protection against hyperoxia involves attenuation of the p53 apoptotic pathway. Hyperoxia stimulated p53-dependent expression of p21 and Bax. Genetic ablation of p21 increased cell death, and loss of Bax or PUMA increased cell survival. Unlike damage caused by adriamycin, whereby p21 sensitivity could be rescued by removal of p53, PUMA, or Bax, increased sensitivity of p21-deficient cells to hyperoxia could not be rescued by additional loss of these genes. Instead, expression of the antiapoptotic protein Bcl-X(L) declined in p21-deficient cells exposed to hyperoxia, but when genetically restored, increased their survival. Conversely, siRNA knockdown of Bcl-X(L) in parental HCT116 cells increased hyperoxia-induced cell death. These findings reveal that p21-mediated protection against hyperoxia does not involve attenuation of p53-dependent apoptosis, but rather functions to maintain Bcl-X(L) expression during periods of persistent oxidative stress.
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PMID:p21(Cip1/Waf1/Sdi1) protects against hyperoxia by maintaining expression of Bcl-X(L). 1686 93

The tumor suppressor protein p53 activates growth arrest and proapoptotic genes in response to DNA damage. It is known that negative feedback by p21(Cip1/Waf1/Sdi1) represses p53-dependent transactivation of PUMA. The current study investigates PUMA feedback on p53 during oxidative stress from hyperoxia and the subsequent effects on cell survival mediated through p21 and Bcl-X(L). Deletion of PUMA in HCT116 colon carcinoma cells increased levels of p53 and p21, resulting in a larger G(1) population during hyperoxia. P21-dependent increase in Bcl-X(L) levels protected PUMA-deficient cells against hyperoxic cell death. Bax and Bak were both able to promote hyperoxic cell death. Bcl-X(L) protection against hyperoxic death was lost in cells lacking Bax, not PUMA, suggesting that Bcl-X(L) acts to inhibit Bax-dependent death. These results indicate that PUMA exerts a negative feedback on p53 and p21, leading to p21-dependent growth suppressive and survival changes. Enhanced survival was associated with increased Bcl-X(L) to block Bax activated cell death during oxidative stress.
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PMID:PUMA inactivation protects against oxidative stress through p21/Bcl-XL inhibition of bax death. 1821 42