AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis.
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.
Department II of Internal Medicine, University Hospital of Cologne, Cologne, Germany.
Katja
K
Höpker
Henning
H
Hagmann
Safiya
S
Khurshid
Shuhua
S
Chen
Pia
P
Hasskamp
Tamina
T
Seeger-Nukpezah
Katharina
K
Schilberg
Lukas
L
Heukamp
Tobias
T
Lamkemeyer
Martin L
ML
Sos
Roman K
RK
Thomas
Drew
D
Lowery
Frederik
F
Roels
Matthias
M
Fischer
Max C
MC
Liebau
Ulrike
U
Resch
Tülay
T
Kisner
Fabian
F
Röther
Malte P
MP
Bartram
Roman Ulrich
RU
Müller
Francesca
F
Fabretti
Peter
P
Kurschat
Björn
B
Schumacher
Matthias
M
Gaestel
René H
RH
Medema
Michael B
MB
Yaffe
Bernhard
B
Schermer
H Christian
HC
Reinhardt
Thomas
T
Benzing
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000502:physiology*; D059447:Cell Cycle Checkpoints; D004249:DNA Damage / Q000235:genetics / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018628:Gene Dosage; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes; D018994:Myosin Light Chains / Q000378:metabolism; D009447:Neuroblastoma / Q000235:genetics / Q000401:mortality; D009997:Osmotic Pressure; D010766:Phosphorylation; D011379:Prognosis; D011499:Protein Processing, Post-Translational; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
C402637:AATF protein, human; D051017:Apoptosis Regulatory Proteins; C577274:MYL12A protein, human; D046912:Multiprotein Complexes; D018994:Myosin Light Chains; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004317:Doxorubicin