Journal
CELL DEATH AND DIFFERENTIATION
Volume 20, Issue 10, Pages 1330-1340Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.83
Keywords
DNA damage response; high cell density; Hippo pathway; c-Abl inhibition; radioresistant
Categories
Funding
- Israel Science Foundation [551/11]
- Israel Cancer Research Fund
- Cooperation Program in Cancer Research of the Deutsches Krebsforschungszentrum (DKFZ)
- Israel's Ministry of Science and Technology (MOST)
- Minerva Foundation
- Federal German Ministry for Education and Research
Ask authors/readers for more resources
The Hippo pathway is an evolutionarily conserved pathway that controls cell proliferation, organ size, tissue regeneration and stem cell self-renewal. Here we show that it also regulates the DNA damage response. At high cell density, when the Hippo pathway is active, DNA damage-induced apoptosis and the activation of the tyrosine kinase c-Abl were suppressed. At low cell density, overexpression of the Hippo pathway kinase large tumor suppressor 2 (Lats2) inhibited c-Abl activity. This led to reduced phosphorylation of downstream c-Abl substrates, the transcription coactivator Yes-associated protein (Yap) and the tumor suppressor p73. Inhibition of c-Abl by Lats2 was mediated through Lats2 interaction with and phosphorylation of c-Abl. Lats2 knockdown, or expression of c-Abl mutants that escape inhibition by Lats2, enabled DNA damage-induced apoptosis of densely plated cells, while Lats2 overexpression inhibited apoptosis in sparse cells. These findings explain a long-standing enigma of why densely plated cells are radioresistant. Furthermore, they demonstrate that the Hippo pathway regulates cell fate decisions in response to DNA damage.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available