Regulation of MCL1 through a serum response factor Elk-1 mediated mechanism links expression of a viability-promoting member of the BCL2 family to the induction of hematopoietic cell differentiation

Proliferation, differentiation, and apoptosis are tightly regulated during hematopoiesis, allowing amplification along specific lineages while prevent ing excessive proliferation of immature cells. The MCL1 member of the BCL2 family is up-regulated during the induction of monocytic differentiation (s imilar to 10-fold with 12-O-tetradecanoylphorbol 13-acetate (TPA)), MCL1 ha s effects similar to those of BCL2, up-regulation promoting viability, but differs from BCL2 in its rapid inducibility and its pattern of expression. Nuclear factors that regulate MCLI transcription have now been identified, extending the previous demonstration of signal transduction through mitogen activated protein kinase, A 162-base pair segment of the human MCLI 5'-fla nk was found to direct luciferase reporter activity, allowing similar to 10 -fold induction with TPA that was suppressible upon inhibition of the extra cellular signal-regulated kinase (ERK) pathway. Serum response factor (SRF) , Elk-1, and Sp1 bound to cownate sites within this segment, SRF and Elk-1 acting coordinately to affect both basal activity and TPA inducibility, whe reas Sp1 affected basal activity only, Thus, the mechanism of the TPA-induc ed increase in MCL1 expression seen in myelomonocytic cells at early stages of differentiation involves signal transduction through ERKs and transcrip tional activation through SRF/Elk-1, This finding provides a parallel to ea rly response genes (e.g. c-FOS and EGR1) that affect maturation commitment in these cells and therefore suggests a means through which enhancement of cell viability may be linked to the induction of differentiation.