Hoepker, Katja, Hagmann, Henning, Khurshid, Safiya, Chen, Shuhua, Hasskamp, Pia, Seeger-Nukpezah, Tamina, Schilberg, Katharina, Heukamp, Lukas ORCID: 0000-0002-3388-3482, Lamkemeyer, Tobias, Sos, Martin L., Thomas, Roman K., Lowery, Drew, Roels, Frederik, Fischer, Matthias, Liebau, Max C., Resch, Ulrike ORCID: 0000-0002-8380-9555, Kisner, Tuelay, Roether, Fabian, Bartram, Malte P., Mueller, Roman Ulrich, Fabretti, Francesca, Kurschat, Peter, Schumacher, Bjoern, Gaestel, Matthias ORCID: 0000-0002-4944-4652, Medema, Rene H., Yaffe, Michael B., Schermer, Bernhard ORCID: 0000-0002-5194-9000, Reinhardt, H. Christian and Benzing, Thomas (2012). AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis. Embo J., 31 (20). S. 3961 - 3976. HOBOKEN: WILEY. ISSN 1460-2075

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Abstract

Following genotoxic stress, cells activate a complex signalling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumour suppressor p53 lies at the heart of this DNA damage response. However, it remains incompletely understood, which signalling molecules dictate the choice between these different cellular outcomes. Here, we identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. Nuclear AATF enrichment appears to be selected for in p53-proficient endometrial cancers. Furthermore, focal copy number gains at the AATF locus in neuroblastoma, which is known to be almost exclusively p53-proficient, correlate with an adverse prognosis and reduced overall survival. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis and commend this pathway as a target for DNA damage-sensitizing therapeutic regimens. The EMBO Journal (2012) 31, 3961-3975. doi:10.1038/emboj.2012.236; Published online 21 August 2012

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Hoepker, KatjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagmann, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Khurshid, SafiyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chen, ShuhuaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hasskamp, PiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seeger-Nukpezah, TaminaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schilberg, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, LukasUNSPECIFIEDorcid.org/0000-0002-3388-3482UNSPECIFIED
Lamkemeyer, TobiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sos, Martin L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lowery, DrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roels, FrederikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebau, Max C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Resch, UlrikeUNSPECIFIEDorcid.org/0000-0002-8380-9555UNSPECIFIED
Kisner, TuelayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roether, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bartram, Malte P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, Roman UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fabretti, FrancescaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kurschat, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gaestel, MatthiasUNSPECIFIEDorcid.org/0000-0002-4944-4652UNSPECIFIED
Medema, Rene H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yaffe, Michael B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Reinhardt, H. ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-480972
DOI: 10.1038/emboj.2012.236
Journal or Publication Title: Embo J.
Volume: 31
Number: 20
Page Range: S. 3961 - 3976
Date: 2012
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; TRANSDUCTION PATHWAYS; P53 TRANSCRIPTION; GENOTOXIC STRESS; IN-VITRO; CHECKPOINT; KINASE; EXPRESSION; CANCER; CHE-1Multiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/48097

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