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Defective BTK expression in leukaemic B\u2010cell precursors from infants with t(4;11) acute lymphoblastic leukaemia has been associated with radiation resistance. The present study examined whether BTK mediates apoptosis during oxidative stress by interfering with the anti\u2010apoptotic function of signal transducer and activator of transcription 3 (STAT3). BTK physically associated with and tyrosine phosphorylated STAT3; this association was promoted by pervanadate (PV)\u2010induced oxidative stress. The BTK\/STAT3 interaction appeared to prevent STAT3 response to oxidative stress, because PV\u2010induced STAT3 activation was markedly enhanced in DT40 chicken lymphoma B\u2010cells that were rendered BTK\u2010deficient by targeted disruption of the <jats:italic>btk<\/jats:italic> gene as well as in BTK\u2010deficient RAMOS\u20101 human lymphoma B\u2010cells. These BTK\u2010deficient cells were highly resistant to oxidative stress\u2010induced apoptosis triggered by PV treatment. Reconstitution of BTK\u2010deficient DT40 cells with wild\u2010type human <jats:italic>BTK<\/jats:italic> gene eliminated the amplification of the STAT3 response and restored the PV\u2010induced apoptotic signal. Similarly, while the BTK\u2010positive NALM\u20106 human leukaemic B\u2010cell precursor cell line showed no STAT3 activation after PV treatment and was exquisitely sensitive to PV\u2010induced apoptosis, PV failed to induce apoptosis in BTK\u2010deficient RAMOS\u20101 human lymphoma B\u2010cells that showed a robust STAT3 response. These results provide unprecedented biochemical and genetic evidence for a unique mode of cross\u2010talk that occurs between BTK and STAT3 pathways during oxidative stress, whereby BTK may trigger apoptosis via negative regulation of the anti\u2010apoptotic STAT3 activity.<\/jats:p>","DOI":"10.1111\/j.1365-2141.2006.06468.x","type":"journal-article","created":{"date-parts":[[2007,1,8]],"date-time":"2007-01-08T11:20:04Z","timestamp":1168255204000},"page":"574-589","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Bruton's tyrosine kinase prevents activation of the anti\u2010apoptotic transcription factor STAT3 and promotes apoptosis in neoplastic B\u2010cells and B\u2010cell precursors exposed to oxidative stress"],"prefix":"10.1111","volume":"136","author":[{"given":"Fatih","family":"Uckun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zahide","family":"Ozer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexei","family":"Vassilev","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2007,1,8]]},"reference":[{"key":"e_1_2_5_2_1","first-page":"316","article-title":"Inhibition of constitutive STAT3 activity sensitizes resistant non\u2010Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug\u2010mediated apoptosis","volume":"9","author":"Alas S.","year":"2003","journal-title":"Clinical Cancer Research"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003-04-1048"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.25.17580"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.278.5344.1803"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(97)80107-0"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/43213"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0505196102"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80501-4"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.99-0913com"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1080\/1042819031000067576"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.3109\/10428199709058334"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.8.4227"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/1074-7613(95)90012-8"},{"key":"e_1_2_5_15_1","first-page":"4410","article-title":"Apurinic endonuclease (Ref\u20101) is induced in mammalian cells by oxidative stress and involved in clastogenic adaptation","volume":"58","author":"Grosch S.","year":"1998","journal-title":"Cancer Research"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200317970"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.16.8563"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.7871432"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.9.8.984"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.1996.0012"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.11.5.558"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0509784103"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V85.2.487.487"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.17.11541"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.25.15595"},{"key":"e_1_2_5_26_1","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0021-9258(17)42492-6","article-title":"Transcriptional induction by interferon. 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