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

    Research output: Contribution to journalArticle

    67 Scopus citations

    Abstract

    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 languageEnglish (US)
    Pages (from-to)524-535
    Number of pages12
    JournalMolecular Cell
    Volume42
    Issue number4
    DOIs
    StatePublished - May 20 2011

    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

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  • Cite this

    Zwang, Y., Sas-Chen, A., Drier, Y., Shay, T., Avraham, R., Lauriola, M., Shema, E., Lidor-Nili, E., Jacob-Hirsch, J., Amariglio, N., Lu, Y., Mills, G. B., Rechavi, G., Oren, M., Domany, E., & Yarden, Y. (2011). Two Phases of Mitogenic Signaling Unveil Roles for p53 and EGR1 in Elimination of Inconsistent Growth Signals. Molecular Cell, 42(4), 524-535. https://doi.org/10.1016/j.molcel.2011.04.017