The RAS-activated RAF→MEK→ERK MAP kinase pathway is an evolutionarily ancient signaling pathway that is critical during development and tissue homeostasis for promoting the cell division cycle leading to cell proliferation but also for terminating the cell division cycle leading to cellular differentiation . However, this pathway also plays a critical role in the initiation and maintenance of a wide variety of human cancers. Experimental evidence suggests that cells are able to integrate the magnitude of ERK MAP kinase signaling over time thereby translating signal strength into disparate, and sometimes opposing, biological outcomes. Using a variety of experimental model systems [2-4] we have explored this paradigm to understand the molecular mechanisms by which this pathway may elicit cell cycle progression versus cell cycle arrest/senescence and have uncovered a potentially important role of the strength of signal pathway activation for the response of human cancer cells to pathway-targeted inhibitors.
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