{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T14:38:18Z","timestamp":1772894298600,"version":"3.50.1"},"reference-count":52,"publisher":"Portland Press Ltd.","issue":"2","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,3,1]]},"abstract":"<jats:p>Chronic inhalation of low amounts of Cr(VI) promotes pulmonary diseases and cancers through poorly defined mechanisms. SFKs (Src family kinases) in pulmonary airway cells may mediate Cr(VI) signalling for lung injury, although the downstream effectors of Cr(VI)-stimulated SFKs and how they relate to pathogenic gene induction are unknown. Therefore SFK-dependent activation of transcription factors by non-cytotoxic exposure of human bronchial epithelial cells to Cr(VI) was determined. Protein\u2013DNA binding arrays demonstrated that exposing BEAS 2B cells to 5\u00a0\u03bcM Cr(VI) for 4 and 24\u00a0h resulted in increased protein binding to 25 and 43 cis-elements respectively, while binding to 12 and 16 cis-elements decreased. Of note, Cr(VI) increased protein binding to several STAT (signal transducer and activator of transcription) cis-elements. Cr(VI) stimulated acute tyrosine phosphorylation and nuclear translocation of STAT1 over a 4\u00a0h period and a prolonged activation of STAT3 that reached a peak between 48 and 72\u00a0h. This prolonged activation was observed for both STAT3\u03b1 and STAT3\u03b2. Immunofluorescent confocal microscopy confirmed that Cr(VI) increased nuclear localization of phosphorylated STAT3 for more than 72\u00a0h in both primary and BEAS 2B human airway cells. Cr(VI) induced transactivation of both a STAT3-driven luciferase reporter construct and the endogenous inflammatory gene IL-6 (interleukin-6). Inhibition with siRNA (small interfering RNA) targeting the SFK Lck, but not dominant-negative JAK (Janus kinase), prevented Cr(VI)-stimulated phosphorylation of both STAT3 isoforms and induction of IL-6. The results suggest that Cr(VI) activates epithelial cell Lck to signal for prolonged STAT3 activation and transactivation of IL-6, an important immunomodulator of lung disease progression.<\/jats:p>","DOI":"10.1042\/bj20061427","type":"journal-article","created":{"date-parts":[[2007,2,15]],"date-time":"2007-02-15T13:56:42Z","timestamp":1171547802000},"page":"261-269","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":27,"title":["Cr(VI)-stimulated STAT3 tyrosine phosphorylation and nuclear translocation in human airway epithelial cells requires Lck"],"prefix":"10.1042","volume":"402","author":[{"given":"Kimberley\u00a0A.","family":"O'hara","sequence":"first","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, 100 Technology Dr, Suite 350, Pittsburgh, PA 15219, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rasilaben\u00a0J.","family":"Vaghjiani","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, 100 Technology Dr, Suite 350, Pittsburgh, PA 15219, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonia\u00a0A.","family":"Nemec","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, 100 Technology Dr, Suite 350, Pittsburgh, PA 15219, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Linda\u00a0R.","family":"Klei","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, 100 Technology Dr, Suite 350, Pittsburgh, PA 15219, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aaron","family":"Barchowsky","sequence":"additional","affiliation":[{"name":"Department of Environmental and Occupational Health, University of Pittsburgh Graduate School of Public Health, 100 Technology Dr, Suite 350, Pittsburgh, PA 15219, U.S.A."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"288","published-online":{"date-parts":[[2007,2,12]]},"reference":[{"key":"2021112213183277400_B1","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/biof.5520110301","article-title":"Is chromium a trace essential metal?","volume":"11","author":"Stearns","year":"2000","journal-title":"Biofactors"},{"key":"2021112213183277400_B2","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1080\/07315724.1999.10718821","article-title":"Mechanisms of chromium action: low-molecular-weight chromium-binding substance","volume":"18","author":"Vincent","year":"1999","journal-title":"J. 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Role of NF-\u03baB and STAT-1 in ozone-induced nitric oxide production and toxicity","volume":"234\u2013235","author":"Laskin","year":"2002","journal-title":"Mol. Cell. Biochem."},{"key":"2021112213183277400_B34","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1183\/09031936.04.00080303","article-title":"STAT4 activation in smokers and patients with chronic obstructive pulmonary disease","volume":"24","author":"Di\u00a0Stefano","year":"2004","journal-title":"Eur. Respir. J."},{"key":"2021112213183277400_B35","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/28101","article-title":"Three-dimensional structure of the Stat3\u03b2 homodimer bound to DNA","volume":"394","author":"Becker","year":"1998","journal-title":"Nature"},{"key":"2021112213183277400_B36","doi-asserted-by":"crossref","first-page":"40594","DOI":"10.1074\/jbc.M203885200","article-title":"JAK-STAT signaling mediates gangliosides-induced inflammatory responses in brain microglial cells","volume":"277","author":"Kim","year":"2002","journal-title":"J. Biol. Chem."},{"key":"2021112213183277400_B37","doi-asserted-by":"crossref","first-page":"5206","DOI":"10.4049\/jimmunol.159.11.5206","article-title":"Constitutive activation of the Janus kinase-STAT pathway in T lymphoma overexpressing the Lck protein tyrosine kinase","volume":"159","author":"Yu","year":"1997","journal-title":"J. Immunol."},{"key":"2021112213183277400_B38","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1289\/ehp.111-1241504","article-title":"Genomic and proteomic profiling of responses to toxic metals in human lung cells","volume":"111","author":"Andrew","year":"2003","journal-title":"Environ. Health Perspect."},{"key":"2021112213183277400_B39","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1023\/A:1017974415052","article-title":"Gene expression profile in response to chromium-induced cell stress in A549 cells","volume":"222","author":"Ye","year":"2001","journal-title":"Mol. Cell. Biochem."},{"key":"2021112213183277400_B40","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/nrm909","article-title":"Stats: transcriptional control and biological impact","volume":"3","author":"Levy","year":"2002","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2021112213183277400_B41","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1172\/JCI6130","article-title":"Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma","volume":"103","author":"Sampath","year":"1999","journal-title":"J. Clin. Invest."},{"key":"2021112213183277400_B42","doi-asserted-by":"crossref","first-page":"7703","DOI":"10.4049\/jimmunol.172.12.7703","article-title":"Stat3 activation in acute lung injury","volume":"172","author":"Gao","year":"2004","journal-title":"J. Immunol."},{"key":"2021112213183277400_B43","doi-asserted-by":"crossref","first-page":"L1282","DOI":"10.1152\/ajplung.00349.2003","article-title":"Activation of the STAT pathway in acute lung injury","volume":"286","author":"Severgnini","year":"2004","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021112213183277400_B44","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1073\/pnas.94.8.3801","article-title":"Targeted disruption of the mouse Stat3 gene leads to early embryonic lethality","volume":"94","author":"Takeda","year":"1997","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112213183277400_B45","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1172\/JCI19491","article-title":"Stat-3 is required for pulmonary homeostasis during hyperoxia","volume":"113","author":"Hokuto","year":"2004","journal-title":"J. Clin. Invest."},{"key":"2021112213183277400_B46","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1385\/CRIAI:28:3:257","article-title":"Pathological role of IL-6 in the experimental allergic bronchial asthma in mice","volume":"28","author":"Doganci","year":"2005","journal-title":"Clin. Rev. Allergy Immunol."},{"key":"2021112213183277400_B47","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1172\/JCI19974","article-title":"Hepatoprotection via the IL-6\/Stat3 pathway","volume":"112","author":"Taub","year":"2003","journal-title":"J. Clin. Invest."},{"key":"2021112213183277400_B48","doi-asserted-by":"crossref","first-page":"5662","DOI":"10.1038\/sj.onc.1203925","article-title":"Janus kinases: components of multiple signaling pathways","volume":"19","author":"Rane","year":"2000","journal-title":"Oncogene"},{"key":"2021112213183277400_B49","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1126\/science.1496401","article-title":"Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor","volume":"257","author":"Schindler","year":"1992","journal-title":"Science"},{"key":"2021112213183277400_B50","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/mc.2940020508","article-title":"Differential effects of chromium(VI) on constitutive and inducible gene expression in chick embryo liver in vivo and correlation with chromium(VI)-induced DNA damage","volume":"2","author":"Hamilton","year":"1989","journal-title":"Mol. Carcinog."},{"key":"2021112213183277400_B51","doi-asserted-by":"crossref","first-page":"4110","DOI":"10.1074\/jbc.M310800200","article-title":"Chromium inhibits transcription from polycyclic aromatic hydrocarbon-inducible promoters by blocking the release of histone deacetylase and preventing the binding of p300 to chromatin","volume":"279","author":"Wei","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112213183277400_B52","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/ni1052","article-title":"The STAT3 isoforms \u03b1 and \u03b2 have unique and specific functions","volume":"5","author":"Maritano","year":"2004","journal-title":"Nat. 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