title: Bcl-2 is the target of a UV-inducible apoptosis switch and a node for UV signaling.
abstract: Sunlight's UVB radiation triggers cell signaling at multiple sites to induce apoptosis. The integration of these signal entry sites is not understood. Here we show that P53 and E2f1 constitute a UV-inducible apoptosis switch. At low-UV doses, wild-type cells resemble the OFF state of an siP53-treated cell, whereas at high-UV doses, the apoptosis frequency transitions to the fully ON behavior of an siE2f1-treated cell. The switch's target is Bcl-2: Rapid Bcl-2 down-regulation in response to UVB-induced DNA photoproducts is lost in P53-deficient cells, but, as for apoptosis, is restored when both P53 and its inhibited target E2f1 are absent. P53's down-regulation of Bcl-2 is mediated entirely through E2f1. Bcl-2 is also down-regulated by a separate pathway triggered by DNA photoproducts in the absence of P53 and E2f1. Four UV pathways terminating on Bcl-2 contribute to apoptosis after UVB irradiation. The apoptosis lost in p53(-/-) is completely restored by siBcl-2, implying that Bcl-2 is a rate-limiting member of this network. These results identify Bcl-2 as an integrator of several UV-induced proapoptotic signals and show that it, in turn, suppresses a direct UV-apoptosis pathway. UV-induced apoptosis requires both UV activation of the direct pathway and a separate UV disinhibition of this pathway through P53-E2f1-Bcl-2.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06525, USA.
authors.forename: Dejan
authors.initials: D
authors.lastname: Knezevic
authors.forename: Wengeng
authors.initials: W
authors.lastname: Zhang
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Rochette
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Brash
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000502:physiology / Q000528:radiation effects; D050687:E2F1 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism* / Q000528:radiation effects*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014466:Ultraviolet Rays
chemical_list: D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53