Universität zu Köln

Morandell, Sandra, Reinhardt, H. Christian, Cannell, Ian G., Kim, Jacob S., Ruf, Daniela M., Mitra, Tanya, Couvillon, Anthony D., Jacks, Tyler and Yaffe, Michael B. (2013). A Reversible Gene-Targeting Strategy Identifies Synthetic Lethal Interactions between MK2 and p53 in the DNA Damage Response In Vivo. Cell Reports, 5 (4). S. 868 - 878. CAMBRIDGE: CELL PRESS. ISSN 2211-1247

Full text not available from this repository.

Abstract

A fundamental limitation in devising new therapeutic strategies for killing cancer cells with DNA damaging agents is the need to identify synthetic lethal interactions between tumor-specific mutations and components of the DNA damage response (DDR) in vivo. The stress-activated p38 mitogen-activated protein kinase (MAPK)/MAPKAP kinase-2 (MK2) pathway is a critical component of the DDR network in p53-deficient tumor cells in vitro. To explore the relevance of this pathway for cancer therapy in vivo, we developed a specific gene targeting strategy in which Cre-mediated recombination simultaneously creates isogenic MK2-proficient and MK2-deficient tumors within a single animal. This allows direct identification of MK2 synthetic lethality with mutations that promote tumor development or control response to genotoxic treatment. In an autochthonous model of non-small-cell lung cancer (NSCLC), we demonstrate that MK2 is responsible for resistance of p53-deficient tumors to cisplatin, indicating synthetic lethality between p53 and MK2 can successfully be exploited for enhanced sensitization of tumors to DNA-damaging chemotherapeutics in vivo.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Morandell, Sandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Reinhardt, H. Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Cannell, Ian G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kim, Jacob S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ruf, Daniela M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mitra, Tanya UNSPECIFIED UNSPECIFIED UNSPECIFIED Couvillon, Anthony D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Jacks, Tyler UNSPECIFIED UNSPECIFIED UNSPECIFIED Yaffe, Michael B. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-473332
DOI:	10.1016/j.celrep.2013.10.025
Journal or Publication Title:	Cell Reports
Volume:	5
Number:	4
Page Range:	S. 868 - 878
Date:	2013
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	2211-1247
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language LUNG-CANCER; THERAPY; INFLAMMATION; KINASE; MICE Multiple languages Cell Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/47333