AATF/Che-1 acts as a phosphorylation-dependent molecular modulator to repress p53-driven apoptosis

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.

Centrosomal Che-1 Protein Is Involved in the Regulation of Mitosis and DNA Damage Response by Mediating Pericentrin (PCNT)-dependent Chk1 Protein Localization

“…Accumulating evidence reveals that in response to several cellular stresses, Che-1 is subjected to post-translational modifications that regulate its functions and localization (11,13). Although we observed that ATM/ATR and Chk2 are not involved in Che-1 centrosomal localization, we cannot exclude that other modifications are responsible for this localization or for its removal from this structure.…”

“…Moreover, in response to DNA damage, ATM-Chk2-phosphorylated Che-1 relocates to the TP53 promoter, activating its transcription and, consequently, that of several p53 target genes (11). It is noteworthy that Che-1 inhibition intensifies the cytotoxicity of DNA-damaging anticancer drugs, in such way reverting the chemoresistance of several tumor cell lines (11)(12)(13). Consistent with these findings, Che-1 depletion strongly decreases mutant p53 expression in human cancer cells, activates DNA damage checkpoint, and induces p73 transcription and apoptosis in these cells (14).…”

Putting the brakes on p53-driven apoptosis

“…45 Höpker and colleagues recently reported data corroborating these observations, showing an enhanced stability of DNA damage-induced cell cycle checkpoints upon overexpression of exogenous AATF. 47 These observations suggest that the effects of AATF overexpression depend at least partially on the activation status of the DDR network with AATF promoting cell cycle progression in the absence of DNA damage and enforcing a cell cycle arrest in response to genotoxic stress. These contrasting effects of AATF signaling correlate with distinct promoter binding of AATF in the different scenarios.…”

AATF Genome: Evolution of Allorecognition

“…AATF was also shown to be a functional antagonist of cell-death inducer (NRAGE) during neuronal development, because its ectopic expression completely reverted NRAGE-induced cell death [1]. Recently, a new dimension was added to the belief that cell-cycle regulators are crucial for cell death by the finding which revealed that AATF had inherent capacity to put brakes on p53-driven apoptosis by binding to the PISMA, BAX and BAK promoters to repress the DNA damageinduced expression of these pro-apoptotic p53 target genes [27]. Strangely, AATF was found to be required for sustaining mutant p53 expression in several cancer cell lines and AATF depletion by siRNA was also accompanied by apoptosis in vitro and in vivo [1], thereby underlining the importance of AATF in survival of cells expressing mutant p53.…”