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Since the first hour of incubation with the proteinase, cells started showing DNA fragmentation, detected by a terminal deoxynucleotidyl transferase\u2010mediated dUDP nick\u2010end labeling (TUNEL)\u2010based photometric enzyme\u2010linked immunosorbent assay (ELISA). At later times, DNA fragments were predominantly located outside the cells, evidencing plasma membrane rupture. DNA fragmentation was completely abolished by Batimastat, a potent inhibitor of metalloproteinase enzymatic activity. Apoptosis induced by BaP1 on endothelial cells was independent of two Bcl\u20102 family members (anti\u2010apototic Bcl\u2010xL and pro\u2010apoptotic Bax), that did not show any changes in their expression during a 24 h\u2010treatment period. Interestingly, I\u03baB\u03b1, an inhibitor of NF\u03baB, decreased after 24 h of treatment, suggesting further activation of the transcription factor. When some elements of the apoptotic extrinsic pathway were assessed, it was observed that procaspase\u20108 completely disappeared after 24 h of treatment with BaP1, probably indicating its activation by a death receptor, whereas caspase\u20108 inhibitor, cellular FLICE\u2010inhibitory protein (cFLIP<jats:sub>L<\/jats:sub>), increased its expression since the first hours of BaP1 incubation. In conclusion, treatment of human endothelial cells with BaP1 induces apoptosis\/anoikis, independently of Bcl\u20102 family members Bax and Bcl\u2010xL and associated with caspase\u20108 activation and cFLIP<jats:sub>L<\/jats:sub> up\u2010regulation. Apoptosis was completely dependent on BaP1 enzymatic activity. Similarities between this and other endothelial cell anoikis\u2010related systems suggest that BaP1 and other snake venom metalloproteinases may be useful experimental tools in the study of death\u2010related events that occur when adherent cells loose contact with extracellular matrix. \u00a9 2004 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.20322","type":"journal-article","created":{"date-parts":[[2004,11,12]],"date-time":"2004-11-12T23:16:54Z","timestamp":1100301414000},"page":"520-528","source":"Crossref","is-referenced-by-count":59,"title":["Characterization of events associated with apoptosis\/anoikis induced by snake venom metalloproteinase BaP1 on human endothelial cells"],"prefix":"10.1002","volume":"94","author":[{"given":"Cecilia","family":"D\u00edaz","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorena","family":"Valverde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Brenes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Rucavado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Guti\u00e9rrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2004,11,12]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.152.3.633"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-0101(01)00249-5"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1006\/abbi.2000.1907"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0163-7258(94)90049-3"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0955-0674(00)00139-3"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20040809"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.10070"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(95)00078-Z"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/cdf356"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-0101(01)00131-3"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/09629350020025728"},{"key":"e_1_2_5_13_1","first-page":"1047","article-title":"Evidence for a function of death\u2010receptor\u2010related, death domain\u2010containing proteins in anoikis","volume":"9","author":"Frisch SM","year":"1999","journal-title":"Curr Opin Cell Biol"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.124.4.619"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0041-0101(02)00359-8"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1015312119693"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0300-9084(00)01163-9"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(94)00138-X"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.1999.00525.x"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(96)00017-7"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.10139"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(94)90302-6"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(95)00029-L"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.1385\/MB:25:3:241"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.3770"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1432-1327.2001.02246.x"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.4.9.953"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M206882200"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-0101(94)90376-X"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830260905"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0049-3848(01)00216-X"},{"key":"e_1_2_5_32_1","first-page":"201","article-title":"Hemorrhagic toxins from rattlesnake (Crotalus atrox) venom. 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