期刊
MOLECULAR CELL
卷 42, 期 4, 页码 524-535出版社
CELL PRESS
DOI: 10.1016/j.molcel.2011.04.017
关键词
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资金
- National Cancer Institute (Cancer Center ) [4R37CA072981, P30 CA16672]
- European Commission
- German-Israeli Project Cooperation
- Israel Cancer Research Fund
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Kekst Family Institute for Medical Genetics
Normal cells require continuous exposure to growth factors in order to cross a restriction point and commit to cell-cycle progression. This can be replaced by two short, appropriately spaced pulses of growth factors, where the first pulse primes a process, which is completed by the second pulse, and enables restriction point crossing. Through integration of comprehensive proteomic and transcriptomic analyses of each pulse, we identified three processes that regulate restriction point crossing: (1) The first pulse induces essential metabolic enzymes and activates p53-dependent restraining processes. (2) The second pulse eliminates, via the PI3K/AKT pathway, the suppressive action of p53, as well as (3) sets an ERK-EGR1 threshold mechanism, which digitizes graded external signals into an all-or-none decision obligatory for S phase entry. Together, our findings uncover two gating mechanisms, which ensure that cells ignore fortuitous growth factors and undergo proliferation only in response to consistent mitogenic signals.
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