{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T08:56:18Z","timestamp":1760345778895},"reference-count":44,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,2,4]],"date-time":"2005-02-04T00:00:00Z","timestamp":1107475200000},"content-version":"vor","delay-in-days":5089,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[1991,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We have previously shown that extracellular ATP acts as a mitogen via protein kinase C (PKC)\u2010dependent and independent pathways (Wang, D., Huang, N., Gonzalez, F.A., and Heppel, L.A. Multiple signal transduction pathways lead to extracellular ATP\u2010stimulated mitogenesis in mammalian cells. I. Involvement of protein kinase C\u2010dependent and independent pathways in the mitogenic response of mammalian cells to extracellular ATP. <jats:italic>J. Cell. Physiol.<\/jats:italic>, 1991). The present aim was to determine if metabolism of arachidonic acid, resulting in prostaglandin E<jats:sub>2<\/jats:sub> (PGE<jats:sub>2<\/jats:sub>) synthesis and elevation of cAMP levels, plays a role in mitogenesis mediated by extracellular ATP. Addition of ATP caused a marked enhancement of cyclic AMP accumulation in 3T3, 3T6, and A431 cells. Aminophylline, an antagonist of the adenosine A<jats:sub>2<\/jats:sub> receptor, had no effect on the accumulation of cyclic AMP elicited by ATP, while it inhibited the action of adenosine. The accumulation of cyclic AMP was concentration dependent, which corresponds to the stimulation of DNA synthesis by ATP. The maximal accumulation was achieved after 45 min, with an initial delay period of about 15 min. That the activation of arachidonic acid metabolism contributed to cyclic AMP accumulation and mitogenesis stimulated by ATP in 3T3, 3T6, and A431 cells was supported by the following observations: (a) extracellular ATP stimulated the release of [<jats:sup>3<\/jats:sup>H]arachidonic acid and PGE<jats:sub>2<\/jats:sub> into the medium; (b) inhibition of arachidonic acid release by inhibitors of phospholipase A<jats:sub>2<\/jats:sub> blocked PGE<jats:sub>2<\/jats:sub> production, cyclic AMP accumulation, and DNA synthesis activated by ATP, and this inhibition could be reversed by adding exogenous arachidonic acid; (c) cyclooxygenase inhibitors, such as indomethacin and aspirin, diminished the release of PGE<jats:sub>2<\/jats:sub> and blocked cyclic AMP accumulation as well as [<jats:sup>3<\/jats:sup>H]thymidine incorporation in response to ATP; (d) PGE<jats:sub>2<\/jats:sub> was able to restore [<jats:sup>3<\/jats:sup>H]thymidine incorporation when added together with ATP in the presence of cyclooxygenase inhibitors; (e) pertussis toxin inhibited ATP\u2010stimulated DNA synthesis in a time\u2010and dose\u2010dependent fashion as well as arachidonic acid release and PGE<jats:sub>2<\/jats:sub> formation. Other evidence for involvement of a pertussis toxin\u2010sensitive G protein(s) in ATP\u2010stimulated DNA synthesis as well as in arachidonic acid release is presented. In A431 cells, the enhancement of arachidonic acid and cyclic AMP accumulation by ATP was partially blocked by PKC down\u2010regulation, implying that the activation of PKC may represent an additional pathway in ATP\u2010stimulated metabolism of arachidonic acid. In all of these studies, ADP and AMP\u2010PNP, but not adenosine, were as active as ATP. In summary, the data support a role for arachidonic acid metabolism in ATP\u2010dependent DNA synthesis in 3T3, 3T6, and A431 cells.<\/jats:p>","DOI":"10.1002\/jcp.1041460320","type":"journal-article","created":{"date-parts":[[2005,2,26]],"date-time":"2005-02-26T08:42:18Z","timestamp":1109407338000},"page":"483-494","source":"Crossref","is-referenced-by-count":42,"title":["Multiple signal transduction pathways lead to extracellular ATP\u2010stimulated mitogenesis in mammalian cells: II. A pathway involving arachidonic acid release, prostaglandin synthesis, and cyclic AMP accumulation"],"prefix":"10.1002","volume":"146","author":[{"given":"Ning\u2010Na","family":"Huang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ding\u2010Ji","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fernando","family":"Gonzalez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Leon A.","family":"Heppel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,2,4]]},"reference":[{"key":"e_1_2_1_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-2236(88)90157-9"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.1041390106"},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.83.19.7201"},{"key":"e_1_2_1_5_1","doi-asserted-by":"crossref","first-page":"11236","DOI":"10.1016\/S0021-9258(18)67373-9","article-title":"\u03b1\u2010Adrenergic stimulation of arachidonic acid release and metabolism in a rat thyroid cell line. 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