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Mol. Biol. Cell 23 (21): 4323-4332

Copyright © 2012 by The American Society for Cell Biology.

Signaling

Nucleolar AATF regulates c-Jun–mediated apoptosis

Saima E. Ferrarisa,b, Kimmo Isoniemia, Elin Torvaldsona,b, Julius Anckara, Jukka Westermarckb,c, and John E. Erikssona,b,1

aDepartment of Biosciences, Åbo Akademi University, FIN-20521 Turku, Finland bTurku Centre for Biotechnology, University of Turku and Åbo Akademi University, FIN-20521 Turku, Finland cDepartment of Pathology, University of Turku, FIN-20520 Turku, Finland

Received for publication May 31, 2012. Revision received August 22, 2012. Accepted for publication August 24, 2012.

Monitoring Editor: Kunxin Luo

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.

This article was published online ahead of print in MBoC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E12-05-0419) on August 29, 2012.

The authors declare no conflict of interest.

1Address correspondence to: John E. Eriksson (john.eriksson{at}abo.fi).

Abbreviations: AATF, apoptosis-antagonizing factor • AP-1, activating protein 1 • ATF, activating factor • TNF α, tumor necrosis factor • FACS, fluorescence-activated cell sorting • GFP, green fluorescent protein • JNK, c-Jun N-terminal kinase • MEF, mouse embryonic fibroblast • RT, reverse transcriptase

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