Two Phases of Mitogenic Signaling Unveil Roles for p53 and EGR1 in Elimination of Inconsistent Growth Signals

Yaara Zwang, Aldema Sas-Chen, Yotam Drier, Tal Shay, Roi Avraham, Mattia Lauriola, Efrat Shema, Efrat Lidor-Nili, Jasmine Jacob-Hirsch, Ninette Amariglio, Yiling Lu, Gordon B. Mills, Gideon Rechavi, Moshe Oren, Eytan Domany, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


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.

Original languageAmerican English
Pages (from-to)524-535
Number of pages12
JournalMolecular Cell
Issue number4
StatePublished - 20 May 2011
Externally publishedYes

Bibliographical note

Funding 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.


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