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.
Bibliographical noteFunding Information:
The authors would like to thank Sara Lavi, Doron Ginsberg, Noa Bossel, Ido Amit, and Ami Citri for their help and Eylon Shahar for technical support. Our research is supported by grants from the National Cancer Institute (including 4R37CA072981, Cancer Center Support Grant, and grant P30 CA16672), the European Commission, the German-Israeli Project Cooperation, the Israel Cancer Research Fund, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Kekst Family Institute for Medical Genetics, and the M.D. Moross Institute for Cancer Research. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair and E.D. of the Henry J. Leir Professorial Chair.