Universität zu Köln

Hoepker, Katja, Hagmann, Henning, Khurshid, Safiya ORCID: 0000-0003-1620-3091, Chen, Shuhua, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Benzing, Thomas and Reinhardt, Hans Christian (2012). Putting the brakes on p53-driven apoptosis. Cell Cycle, 11 (22). S. 4122 - 4129. PHILADELPHIA: TAYLOR & FRANCIS INC. ISSN 1551-4005

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Abstract

Following genotoxic stress, cells activate a complex, kinase-based signaling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumor suppressor p53 lies at the heart of this DNA damage response. p53 mediates the transactivation of both cell cycle-regulating and pro-apoptotic clusters of target genes. However, it remains incompletely understood which signaling molecules dictate the choice between these two opposing p53-dependent cellular outcomes. Over recent years, numerous regulatory mechanisms impacting on the cellular outcome of p53 signaling have been described. However, no single dominant mechanism has thus far been identified to regulate the cellular choice between p53-driven apoptosis or senescence. The transcriptional regulator AATF has recently emerged as a novel factor impacting on the cellular outcome of the p53 response. Upon genotoxic stress, cytoplasmic pools of MRLC-bound AATF are phosphorylated through the p38MAPK/MK2 checkpoint kinase complex. This AATF phosphorylation results in the disruption of cytoplasmic MRLC3: AATF complexes followed by rapid nuclear localization of AATF. Once in the nucleus, AATF binds to the PUMA, BAX and BAK promoters to repress the DNA damage-induced expression of these pro-apoptotic p53 target genes. Depletion of AATF in tumor cells results in a dramatically enhanced response to DNA damaging chemotherapeutics, both in vitro and in vivo. Furthermore, focal copy number gains at the AATF locus in neuroblastoma correlate with adverse prognosis and reduced overall survival in this typically p53-proficient malignancy. These data identify the p38/MK2/AATF signaling pathway as a critical repressor of p53-driven apoptosis in tumor cells and implicate this signaling cascade as a novel target for chemotherapy-sensitizing therapeutic efforts.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoepker, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hagmann, Henning UNSPECIFIED UNSPECIFIED UNSPECIFIED Khurshid, Safiya UNSPECIFIED orcid.org/0000-0003-1620-3091 UNSPECIFIED Chen, Shuhua UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-478906
DOI:	10.4161/cc.21997
Journal or Publication Title:	Cell Cycle
Volume:	11
Number:	22
Page Range:	S. 4122 - 4129
Date:	2012
Publisher:	TAYLOR & FRANCIS INC
Place of Publication:	PHILADELPHIA
ISSN:	1551-4005
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; CELL-CYCLE ARREST; POTENTIAL MEDIATOR; P53 TRANSCRIPTION; CHK2 KINASES; IN-VITRO; CHECKPOINT; PATHWAY; PHOSPHORYLATION; CANCER Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47890