Lessons learned in model differentiation systems, such as the lineage uncommitted human myeloblastic leukemia cell line HL-60, could inform the analysis of more complex differentiation programs. HL-60 undergoes myeloid differentiation and G1/0-arrest following persistent MAPK activation, when exposed to All-Trans Retinoic Acid (ATRA). The architecture responsible for ATRA-induced persistent MAPK activation, commitment, cell-cycle arrest and differentiation, as well as pretreatment memory effects, is poorly understood. To this end, we measured interactions between cRaf and a panel of possible cRaf interaction partners with and without ATRA and the cRaf inhibitor GW5074. From this survey, we identified a signaling circuit capable of initiating persistent MAPK signaling following RA-exposure. We then showed that this architecture explained both persistent MAPK activation and ATRA memory effects in HL-60 cells. Taken together, these studies identified a key differentiation initiation circuit whose organization might be broadly important.

Investigation of the cRaf interactome and steady-state multiplicity in Retinoic Acid induced differentiation of HL-60 cells

243rd National Meeting (2012)

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