title: Bax deficiency affects caspase-2 activation during ultraviolet radiation-induced apoptosis.
abstract: There has been a considerable debate as to whether caspase-2 is an initiator or effector caspase. Recently, a new model of intrinsic pathway of apoptosis has been proposed, which suggests caspase-2 to be an initiator caspase. For example, ultraviolet radiation (UV) and other DNA damage-inducing agents were shown to first activate caspase-2 and then regulate the mitochondrial and postmitochondrial events. Active caspase-2 was found to engage mitochondria by promoting Bax translocation to the mitochondria. Consequently, Bax was proposed to play a central role in bridging the active caspase-2 with mitochondria by affecting mitochondrial permeability, cytochrome c release into the cytosol and caspase-9 activation. In the present study, we investigated the role of Bax in UV-induced apoptosis and caspase-2 activation. Our results indicate that UV-induced apoptosis and caspase-2 activation were diminished in Bax-deficient cells, suggesting that Bax appears to play an important role in UV-induced apoptosis as well as caspase-2 activation, and that it also appears to reside upstream of caspase-2. Bax deficiency also affected the activation of caspase-3 and -8 and abolished caspase-9 activation during UV-induced apoptosis, suggesting that the absence of caspase-9 activation may affect caspase-2, -3 and -8 activation in Bax-deficient cells. Based on our results, we propose that activation of caspases is not a linear cascade of events, but is rather connected via complex feedback loops.
authors.affiliation: Department of Pharmacology, State University of New York, Upstate Medical University, 750 E Adams Street, Syracuse, NY 13210, USA.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.forename: Ying
authors.initials: Y
authors.lastname: Huang
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Sheikh
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects*; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D017353:Gene Deletion; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays; D051028:bcl-2-Associated X Protein
chemical_list: C494826:BAX protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D053143:Caspase 2; D020169:Caspases