EXPRESSION OF THE ANTIAPOPTOTIC MCL1 GENE-PRODUCT IS REGULATED BY A MITOGEN-ACTIVATED PROTEIN KINASE-MEDIATED PATHWAY TRIGGERED THROUGH MICROTUBULE DISRUPTION AND PROTEIN-KINASE-C

Members of both the mitogen activated protein (MAP) kinase and BCL2 ge ne families, acting in concert with other gene products, are involved in the regulation of cell viability. However, the relationship between these families, and the signal transduction networks that control via bility-regulating genes, are only beginning to be elucidated, MCL1 is a viability-promoting member of the BCL2 family that exhibits a rapid increase in expression in response to specific differentiation- and ap optosis-inducing stimuli. The signal transduction pathway involved in eliciting this increase has now been investigated. In the ML-1 human m yeloblastic leukemia cell line, a rapid and sustained increase in phos phorylation of the extracellular signal-regulated kinase (ERK) members of the MAP kinase family was found to precede the increase in MCL1 ex pression produced by 12-O-tetradecanoylphorbol 13-acetate (TPA) or the microtubule-disrupting agents colchicine and vinblastine. ERK activat ion was necessary for the increase in MCL1, as inhibition of the incre ase in ERK phosphorylation (with the inhibitor PD 98059) prevented the increase in MCL1 expression and caused rapid cell death by apoptosis, In addition, other agents that markedly increased ERK phosphorylation (lipopolysaccharide, okadaic acid) also increased MCL1 expression. In contrast, agents that did not have this marked effect did not increas e MCL1, Upstream components in this ERK-mediated pathway were also ide ntified, where the pathway was found to be stimulated by microtubule d isruption acting through protein kinase C (PKC). These results indicat e that expression of the MCL1 viability-enhancing gene is regulated th rough a cytoskeletal disruption-induced ERK-mediated signal, transduct ion pathway. They therefore suggest a mechanism through which the cyto skeleton and MAP kinases can exert effects on cell viability.