{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:24:51Z","timestamp":1791055491530,"version":"4.1.0"},"reference-count":28,"publisher":"American Physiological Society","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal of Applied Physiology"],"published-print":{"date-parts":[[2000,5,1]]},"abstract":"<jats:p>In the present study we examined the intracellular pathways that link hypoxia to activation of c- fosgene expression. Experiments were performed on rat pheocromocytoma-12 (PC-12) cells. c- fos mRNA and promoter activities were analyzed by RT-PCR and reporter gene assays, respectively. BAPTA, a Ca<jats:sup>2+<\/jats:sup>chelator, inhibited c- fos mRNA and promoter activation by hypoxia. Nitrendipine, an L-type Ca<jats:sup>2+<\/jats:sup>-channel blocker, abolished, whereas BAY K 8644, an L-type channel agonist, enhanced c- fos activation by hypoxia. Ca<jats:sup>2+<\/jats:sup>currents were augmented reversibly by hypoxia, suggesting that Ca<jats:sup>2+<\/jats:sup>influx mediated by L-type Ca<jats:sup>2+<\/jats:sup>channels is essential for c- fos activation by hypoxia. We next determined downstream pathways activated by intracellular Ca<jats:sup>2+<\/jats:sup>concentration. Immunoblot analysis revealed Ca<jats:sup>2+<\/jats:sup>\/calmodulin-dependent kinase II (CaMKII) protein in PC-12 cells and revealed that hypoxia increased the enzyme activity. KN-93, a CaMK inhibitor, blocked CaMKII activation and c- fos promoter stimulation by hypoxia. Ectopic expression of an active mutant of CaMKII (pCaMKII290) stimulated c- fos promoter activity under normoxia. Hypoxia increased phosphorylation of CREB at the serine residue 133 (Ser-133), and KN-93 attenuated this effect. Point mutations at the Ca<jats:sup>2+<\/jats:sup>\/cAMP-responsive cis-element (Ca\/CRE) attenuated, whereas point mutations in the serum-responsive cis-element (SRE) abolished transcriptional activation of c- fos by hypoxia. These results demonstrate that c- fosactivation by hypoxia involves CaMK activation and CREB phosphorylation at Ser-133 and requires Ca\/CRE and SRE. These observations demonstrate that Ca<jats:sup>2+<\/jats:sup>-dependent signaling pathways play a crucial role in induction of c- fos gene expression, which may underlie long-term adaptive responses to hypoxia.<\/jats:p>","DOI":"10.1152\/jappl.2000.88.5.1898","type":"journal-article","created":{"date-parts":[[2017,12,23]],"date-time":"2017-12-23T00:45:55Z","timestamp":1513989955000},"page":"1898-1906","source":"Crossref","is-referenced-by-count":37,"title":["L-type Ca<sup>2+<\/sup>channel activation regulates induction of c-<i>fos<\/i>transcription by hypoxia"],"prefix":"10.1152","volume":"88","author":[{"given":"Daniel R. 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