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

Kelly D. Sullivan, Nuria Padilla-Just, Ryan E. Henry, Christopher C. Porter, Jihye Kim, John J. Tentler, S. Gail Eckhardt, Aik-Choon Tan, James DeGregori, Joaquín M. Espinosa

Research output: Contribution to journalArticle

51 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)646-654
Number of pages9
JournalNature Chemical Biology
Volume8
Issue number7
DOIs
Publication statusPublished - 2012 Jul 1
Externally publishedYes

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Phosphotransferases
Cell Cycle Checkpoints
Neoplasms
Lethal Genes
Apoptosis
p53 Genes
Small Interfering RNA
Genome
Pharmacology
Therapeutics
nutlin 3

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Sullivan, K. D., Padilla-Just, N., Henry, R. E., Porter, C. C., Kim, J., Tentler, J. J., ... Espinosa, J. M. (2012). ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nature Chemical Biology, 8(7), 646-654. https://doi.org/10.1038/nchembio.965

ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. / Sullivan, Kelly D.; 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.

In: Nature Chemical Biology, Vol. 8, No. 7, 01.07.2012, p. 646-654.

Research output: Contribution to journalArticle

Sullivan, KD, Padilla-Just, N, Henry, RE, Porter, CC, Kim, J, Tentler, JJ, Eckhardt, SG, Tan, A-C, DeGregori, J & Espinosa, JM 2012, 'ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53', Nature Chemical Biology, vol. 8, no. 7, pp. 646-654. https://doi.org/10.1038/nchembio.965
Sullivan KD, Padilla-Just N, Henry RE, Porter CC, Kim J, Tentler JJ et al. ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. Nature Chemical Biology. 2012 Jul 1;8(7):646-654. https://doi.org/10.1038/nchembio.965
Sullivan, Kelly D. ; 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. / ATM and MET kinases are synthetic lethal with nongenotoxic activation of p53. In: Nature Chemical Biology. 2012 ; Vol. 8, No. 7. pp. 646-654.
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