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PMID: 22660439 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53.

Nature chemical biology ·Vol. 8 ·No. 7 ·2012-07-00 ·Pages 646-54

Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, Tentler JJ, Eckhardt SG, Tan AC, DeGregori J, Espinosa JM

Abstract

The p53 tumor suppressor orchestrates alternative stress responses including cell cycle arrest and apoptosis, but the mechanisms defining cell fate upon p53 activation are poorly understood. Several small-molecule activators of p53 have been developed, including Nutlin-3, but their therapeutic potential is limited by the fact that they induce reversible cell cycle arrest in most cancer cell types. We report here the results of a genome-wide short hairpin RNA screen for genes that are lethal in combination with p53 activation by Nutlin-3, which showed that the ATM and MET kinases govern cell fate choice upon p53 activation. Genetic or pharmacological interference with ATM or MET activity converts the cellular response from cell cycle arrest into apoptosis in diverse cancer cell types without affecting expression of key p53 target genes. ATM and MET inhibitors also enable Nutlin-3 to kill tumor spheroids. These results identify new pathways controlling the cellular response to p53 activation and aid in the design of p53-based therapies.

MeSH Terms
Apoptosis/genetics Ataxia Telangiectasia Mutated Proteins Cell Cycle Cell Cycle Proteins/genetics,metabolism Cell Line DNA-Binding Proteins/genetics,metabolism Genes, Lethal Genes, Synthetic Genes, p53 Humans Imidazoles/metabolism Piperazines/metabolism Protein Serine-Threonine Kinases/genetics,metabolism Proto-Oncogene Proteins c-met/genetics,metabolism Tumor Suppressor Proteins/genetics,metabolism
Chemicals
Cell Cycle Proteins DNA-Binding Proteins Imidazoles Piperazines Tumor Suppressor Proteins nutlin 3 MET protein, human Proto-Oncogene Proteins c-met ATM protein, human Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Sullivan Kelly D
Howard Hughes Medical Institute, University of Colorado at Boulder, Boulder, Colorado, USA.
Padilla-Just Nuria
Henry Ryan E
Porter Christopher C
Kim Jihye
Tentler John J
Eckhardt S Gail
Tan Aik Choon
DeGregori James
Espinosa Joaquín M
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Article Info
Journal
Nature chemical biology
Abbr.
Nat Chem Biol
ISSN
1552-4469
DOI
10.1038/nchembio.965
Published
2012-07-00
Epub
2012-00-03
Pages
646-54
Language
English
Region
United States
NLM ID
101231976
PMCID
PMC3430605
Subset
IM
Grants
NCI NIH HHS · P50 CA058187 · United States
NCI NIH HHS · R01 CA117907 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · R01 CA157850 · United States
NCI NIH HHS · T32 CA082086 · United States
NCI NIH HHS · P30 CA046934 · United States
External Links
PubMed source DOI: 10.1038/nchembio.965 PMC Full Text View journal details
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