{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T19:17:17Z","timestamp":1790191037329,"version":"4.1.0"},"reference-count":46,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2001,12,14]],"date-time":"2001-12-14T00:00:00Z","timestamp":1008288000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Journal Cellular Physiology"],"published-print":{"date-parts":[[2002,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In a previous work, we have shown that overexpression of the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter (NKCC1) induces cell proliferation and transformation. We investigate in the present study the role of the NKCC1 in the mitogenic signal transduction. We show that overexpression of the cotransporter gene (NKCC1) in stablely transfected cells (Balb\/c\u2010NKCC1), resulted in enhanced phosphorylation of the extracellular regulated kinase (ERK) to produce double phosphorylated ERK (DP\u2010ERK). Furthermore, the level of DP\u2010ERK was reduced by 50\u201380% following the addition of bumetanide, a specific inhibitor of the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter, in quiescent as well as in proliferating cultures of the Balb\/c\u2010NKCC1 clone. In order to explore further the role of the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter in mitogenic signal transduction, we measured the effect of the two specific inhibitors of the cotransporter; bumetanide and furosemide, on DP\u2010ERK level in immortalized non\u2010transformed cells. In Balb\/c 3T3 fibroblasts stimulated with FGF, bumetanide, and furosemide inhibited 50\u201360% of the ERK 1\/2 phosphorylation. The inhibitor concentration needed for maximal inhibition of ERK 1\/2 phosphorylation was similar to the concentration needed to block the K<jats:sup>+<\/jats:sup> influx mediated by the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter in these cells. To analyze whether the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter has a role in the mitogenic signal of normal cells, we measured the effect of bumetanide on ERK phosphorylation in human peripheral blood lymphocytes. The phosphorylation of ERK 1\/2 in resting human lymphocytes, as well as in lymphocytes stimulated with phytohemagglutinin (PHA) was inhibited by bumetanide. The effect of bumetanide on ERK 2 phosphorylation was much lower than that of ERK 1 phosphorylation. The finding that the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter controls the ERK\/MAPK (mitogen\u2010activated protein kinase) signal transduction pathway, support our hypothesis that Na<jats:sup>+<\/jats:sup> and K<jats:sup>+<\/jats:sup> influxes mediated by this transporter plays a central role in the control of normal cell proliferation. Exploring the cellular ionic currents and levels, mediated by the Na<jats:sup>+<\/jats:sup>\/K<jats:sup>+<\/jats:sup>\/Cl<jats:sup>\u2212<\/jats:sup> cotransporter, should lead to a better comprehension of cell proliferation and transformation machinery. J. Cell. Physiol. 190: 227\u2013237, 2002. \u00a9 2002 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcp.10055","type":"journal-article","created":{"date-parts":[[2002,8,25]],"date-time":"2002-08-25T22:11:41Z","timestamp":1030313501000},"page":"227-237","source":"Crossref","is-referenced-by-count":28,"title":["Na<sup>+<\/sup>\/K<sup>+<\/sup>\/Cl<sup>\u2212<\/sup> cotransporter activates mitogen\u2010activated protein kinase in fibroblasts and 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