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 gene 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 viability-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 apoptosis-inducing stimuli. The signal transduction pathway involved in eliciting this increase has now been investigated. In the ML-1 human myeloblastic leukemia cell line, a rapid and sustained increase in phosphorylation of the extracellular signal-regulated kinase (ERK) members of the MAP kinase family was found to precede the increase in MCL1 expression produced by 12-O-tetradecanoylphorbol 13-acetate (TPA) or the microtubule-disrupting agents colchicine and vinblastine. ERK activation was necessary for the increase in MCL1, as inhibition of the increase 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 increase MCL1. Upstream components in this ERK-mediated pathway were also identified, where the pathway was found to be stimulated by microtubule disruption acting through protein kinase C (PKC). These results indicate that expression of the MCL1 viability-enhancing gene is regulated through a cytoskeletal disruption-induced ERK-mediated signal transduction pathway. They therefore suggest a mechanism through which the cytoskeleton and MAP kinases can exert effects on cell viability.
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 03755-3835, USA.
K J
KJ
Townsend
J L
JL
Trusty
M A
MA
Traupman
A
A
Eastman
R W
RW
Craig
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology; D003078:Colchicine / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000494:pharmacology
D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014747:Vinblastine; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D017239:Paclitaxel; D002945:Cisplatin; D003078:Colchicine