title: Nucleolar AATF regulates c-Jun-mediated apoptosis.
abstract: The AP-1 transcription factor c-Jun has been shown to be essential for stress-induced apoptosis in several models. However, the molecular mechanisms underlying the proapoptotic activity of c-Jun are poorly understood. We identify the apoptosis-antagonizing transcription factor (AATF) as a novel nucleolar stress sensor, which is required as a cofactor for c-Jun-mediated apoptosis. Overexpression or down-regulation of AATF expression levels led to a respective increase or decrease in the amount of activated and phosphorylated c-Jun with a proportional alteration in the induction levels of the proapoptotic c-Jun target genes FasL and TNF-α. Accordingly, AATF promoted commitment of ultraviolet (UV)-irradiated cells to c-Jun-dependent apoptosis. Whereas AATF overexpression potentiated UV-induced apoptosis in wild-type cells, c-Jun-deficient mouse embryonic fibroblasts were resistant to AATF-mediated apoptosis induction. Furthermore, AATF mutants defective in c-Jun binding were also defective in inducing AP-1 activity and c-Jun-mediated apoptosis. UV irradiation induced a translocation of AATF from the nucleolus to the nucleus, thereby enabling its physical association to c-Jun. Analysis of AATF deletion mutants revealed that the AATF domains required for compartmentalization, c-Jun binding, and enhancement of c-Jun transcriptional activity were all also required to induce c-Jun-dependent apoptosis. These results identify AATF as a nucleolar-confined c-Jun cofactor whose expression levels and spatial distribution determine the stress-induced activity of c-Jun and the levels of c-Jun-mediated apoptosis.
authors.affiliation: Department of Biosciences, Åbo Akademi University, FIN-20521 Turku, Finland.
authors.forename: Saima E
authors.initials: SE
authors.lastname: Ferraris
authors.forename: Kimmo
authors.initials: K
authors.lastname: Isoniemi
authors.forename: Elin
authors.initials: E
authors.lastname: Torvaldson
authors.forename: Julius
authors.initials: J
authors.lastname: Anckar
authors.forename: Jukka
authors.initials: J
authors.lastname: Westermarck
authors.forename: John E
authors.initials: JE
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D002466:Cell Nucleolus / Q000378:metabolism* / Q000528:radiation effects; D004622:Embryo, Mammalian / Q000166:cytology; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000528:radiation effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C402637:AATF protein, human; C417216:Aatf protein, mouse; D051017:Apoptosis Regulatory Proteins; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D012097:Repressor Proteins