{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T02:10:15Z","timestamp":1791252615559,"version":"4.1.0"},"reference-count":39,"publisher":"American Physiological Society","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"published-print":{"date-parts":[[2004,1]]},"abstract":"<jats:p>\n                    Hyperoxia has been shown to cause DNA damage resulting in growth arrest of cells in p53-dependent, as well as p53-independent, pathways. Although H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    and other peroxides have been shown to induce ataxia telangiectasia-mutated (ATM)-dependent p53 phosphorylation in response to DNA damage, the signal transduction mechanisms in response to hyperoxia are currently unknown. Here we demonstrate that hyperoxia phosphorylates the Ser15 residue of p53 independently of ATM. Hyperoxia phosphorylated p53 (Ser15) in DNA-dependent protein kinase null (DNA-PK\n                    <jats:sup>-\/-<\/jats:sup>\n                    ) cells, indicating that it may not depend on DNA-PK for phosphorylation of p53 (Ser15). We show that Ser37 and Ser392 residues of p53 are also phosphorylated in an ATM-independent manner in hyperoxia. In contrast, H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    did not phosphorylate Ser37 in either ATM\n                    <jats:sup>+\/+<\/jats:sup>\n                    or ATM\n                    <jats:sup>-\/-<\/jats:sup>\n                    cells. Furthermore, H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    failed to phosphorylate Ser15 in ATM\n                    <jats:sup>-\/-<\/jats:sup>\n                    cells. Additionally, overexpression of kinase-inactive ATM-and-Rad3-related (ATR) in HEK293T cells diminished Ser15, Ser37, and Ser392 phosphorylation compared with vector-only transfected cells. In contrast, wild-type ATR overexpression did not diminish Ser15, Ser37, or Ser392 phosphorylation. We also show that checkpoint kinase 1 (Chk1) is phosphorylated on Ser345 in response to hyperoxia, which could be inhibited by caffeine or wortmannin, potent inhibitors of phosphoinositide 3-kinase-related kinases. Hyperoxia also phosphorylated Chk1 in ATM\n                    <jats:sup>+\/+<\/jats:sup>\n                    as well as in ATM\n                    <jats:sup>-\/-<\/jats:sup>\n                    cells, demonstrating an ATM-independent mechanism in Chk1 phosphorylation. Together, our data suggest that hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites in an ATM-independent manner, which is different from other forms of oxidative stress such as H\n                    <jats:sub>2<\/jats:sub>\n                    O\n                    <jats:sub>2<\/jats:sub>\n                    or UV light.\n                  <\/jats:p>","DOI":"10.1152\/ajplung.00203.2002","type":"journal-article","created":{"date-parts":[[2004,1,30]],"date-time":"2004-01-30T19:55:58Z","timestamp":1075492558000},"page":"L87-L97","source":"Crossref","is-referenced-by-count":45,"title":["Hyperoxia activates the ATR-Chk1 pathway and phosphorylates p53 at multiple sites"],"prefix":"10.1152","volume":"286","author":[{"given":"Kumuda C.","family":"Das","sequence":"first","affiliation":[{"name":"Department of Molecular Biology, University of Texas Health Center at Tyler, Tyler, Texas 75703"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Dashnamoorthy","sequence":"additional","affiliation":[{"name":"Department of Molecular Biology, University of Texas Health Center at Tyler, Tyler, Texas 75703"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"24","reference":[{"key":"REF1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.914401"},{"key":"REF2","doi-asserted-by":"publisher","DOI":"10.1126\/science.281.5383.1674"},{"key":"REF3","doi-asserted-by":"crossref","unstructured":"Brown EJ\n                      and Baltimore D.\n                      ATR disruption leads to chromosomal fragmentation and early embryonic lethality.\n                      Genes Dev\n                      14\n                      : 397-402, 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2000.","DOI":"10.1101\/gad.14.3.289"},{"key":"REF36","doi-asserted-by":"publisher","DOI":"10.1101\/gad.13.2.152"},{"key":"REF37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104157200"},{"key":"REF38","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.13.4129-4139.2001"},{"key":"REF39","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(89)80881-6"}],"container-title":["American Journal of Physiology-Lung Cellular and Molecular Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.physiology.org\/doi\/pdf\/10.1152\/ajplung.00203.2002","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,27]],"date-time":"2023-04-27T16:21:31Z","timestamp":1682612491000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.physiology.org\/doi\/10.1152\/ajplung.00203.2002"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,1]]},"references-count":39,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2004,1]]}},"alternative-id":["10.1152\/ajplung.00203.2002"],"URL":"https:\/\/doi.org\/10.1152\/ajplung.00203.2002","relation":{},"ISSN":["1040-0605","1522-1504"],"issn-type":[{"value":"1040-0605","type":"print"},{"value":"1522-1504","type":"electronic"}],"subject":[],"published":{"date-parts":[[2004,1]]}}}