Universität zu Köln

Welcker, Daniela, Jain, Manaswita ORCID: 0000-0002-5107-7505, Khurshid, Safiya ORCID: 0000-0003-1620-3091, Jokic, Mladen, Hoehne, Martin, Schmitt, Anna, Frommolt, Peter ORCID: 0000-0002-1966-8014, Niessen, Carien M., Spiro, Judith, Persigehl, Thorsten, Wittersheim, Maike, Buettner, Reinhard, Fanciulli, Maurizio, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Reinhardt, Hans Christian, Benzing, Thomas and Hoepker, Katja (2018). AATF suppresses apoptosis, promotes proliferation and is critical for Kras-driven lung cancer. Oncogene, 37 (11). S. 1503 - 1519. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5594

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Abstract

A fundamental principle in malignant tranformation is the ability of cancer cells to escape the naturally occurring cellintrinsic responses to DNA damage. Tumors progress despite the accumulation of DNA lesions. However, the underlying mechanisms of this tolerance to genotoxic stress are still poorly characterized. Here, we show that replication stress occurs in Kras-driven murine lung adenocarcinomas, as well as in proliferating murine embryonic and adult tissues. We identify the transcriptional regulator AATF/CHE-1 as a key molecule to sustain proliferative tissues and tumor progression in parts by inhibiting p53-driven apoptosis in vivo. In an autochthonous Kras-driven lung adenocarcinoma model, deletion of Aatf delayed lung cancer formation predominantly in a p53-dependent manner. Moreover, targeting Aatf in existing tumors through a dual recombinase strategy caused a halt in tumor progression. Taken together, these data suggest that AATF may serve as a drug target to treat KRAS-driven malignancies.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Welcker, Daniela UNSPECIFIED UNSPECIFIED UNSPECIFIED Jain, Manaswita UNSPECIFIED orcid.org/0000-0002-5107-7505 UNSPECIFIED Khurshid, Safiya UNSPECIFIED orcid.org/0000-0003-1620-3091 UNSPECIFIED Jokic, Mladen UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoehne, Martin UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmitt, Anna UNSPECIFIED UNSPECIFIED UNSPECIFIED Frommolt, Peter UNSPECIFIED orcid.org/0000-0002-1966-8014 UNSPECIFIED Niessen, Carien M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Spiro, Judith UNSPECIFIED UNSPECIFIED UNSPECIFIED Persigehl, Thorsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Wittersheim, Maike UNSPECIFIED UNSPECIFIED UNSPECIFIED Buettner, Reinhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Fanciulli, Maurizio UNSPECIFIED UNSPECIFIED UNSPECIFIED Schermer, Bernhard UNSPECIFIED orcid.org/0000-0002-5194-9000 UNSPECIFIED Reinhardt, Hans Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Benzing, Thomas UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoepker, Katja UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-194470
DOI:	10.1038/s41388-017-0054-6
Journal or Publication Title:	Oncogene
Volume:	37
Number:	11
Page Range:	S. 1503 - 1519
Date:	2018
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5594
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language DNA-DAMAGE RESPONSE; CELL-CYCLE; RAS ONCOGENES; P53 TRANSCRIPTION; CHK2 KINASES; CHECKPOINT; CHE-1; ATM; PATHWAY; GROWTH Multiple languages Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/19447