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

Abstract

Proliferation, differentiation, and apoptosis are tightly regulated during hematopoiesis, allowing amplification along specific lineages while preventing excessive proliferation of immature cells. The MCL1 member of the BCL2 family is up-regulated during the induction of monocytic differentiation (ϳ10-fold with 12-O-tetradecanoylphorbol 13-acetate (TPA)). MCL1 has 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 MCL1 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 MCL1 5-flank was found to direct luciferase reporter activity, allowing ϳ10-fold induction with TPA that was suppressible upon inhibition of the extracellular signal-regulated kinase (ERK) pathway. Serum response factor (SRF), Elk-1, and Sp1 bound to cognate sites within this segment, SRF and Elk-1 acting coordinately to affect both basal activity and TPA inducibility, whereas Sp1 affected basal activity only. Thus, the mechanism of the TPA-induced increase in MCL1 expression seen in myelomonocytic cells at early stages of differentiation involves signal transduction through ERKs and transcriptional activation through SRF/Elk-1. This finding provides a parallel to early 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.

Activation of the EphA2 tyrosine kinase stimulates the MAP/ERK kinase signaling cascade

“…SHC, in turn, bridges EphA2 to GRB2, which facilitates the activation and nuclear translocation of ERK kinases, where they induce the Elk-1 transcription factor kinase, SLAP, SHP2 and FAK (Miao et al, 2000;Pandey et al, 1994Pandey et al, , 1995a, whereas our present study extends signaling from EphA2 at the cell membrane to the nucleus. The induction of Elk-1 is also interesting since ERK stimulation of Elk-1 has been linked with both the postive and negative regulation of cell proliferation and differentiation (Brunet et al, 1995;Clarkson et al, 1999;Davis, 1995;Lin et al, 1997;Macleod et al, 1992;Townsend et al, 1999;Treisman, 1994;Vanhoutte et al, 2001). Although the biological consequences of Elk-1 induction by EphA2 are presently unknown, ligand-mediated activation of EphA2 has been linked with the negative regulation of numerous biological outcomes, including the regulation of cell proliferation, survival, migration, invasion, differentiation and angiogenesis (Miao et al, 2000(Miao et al, , 2001Pandey et al, 1995a,b;Rosenberg et al, 1997;Zantek et al, 1999;Zelinski et al, 2001).…”

MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis

“…15 This pathway results in the activation of a transcription factor complex that contains serum response factor (SRF) and Elk-1 and that is bound to the human MCL1 promoter upstream of the start site of transcription. 82 MAP kinase mediated pathways (either MEK/ERK or p38) are also involved in the induction of MCL1 expression in other systems. [83][84][85] An additional pathway, transduced through phosphatidylinositol 3-kinase (PI3K) and AKT, is involved in the induction of MCL1 expression by GM-CSF and IL-3 in hematopoietic progenitor cells.…”

Impact of Phospho-ELK-1 Expression in Enterocytes in Biodosimetry after Low-dose Irradiation

“…However, generally lower p-ELK-1 expression was observed in low-differentiated cells localised between mucous plicas than in mature and well-differentiated cells at the top of mucous plicas.Therefore, p-ELK-1 expression might be directly dependent on cell differentiation and for practical biodosimetric evaluation it should be measured in the most differentiated part of mucosa. Probable explanation was published by Townsend 18 , et al, who measured proliferative and differentiation effect of MCL-1, the ELK-1-mediated protein, to immature monocytes is that ELK-1-mediated up-regulation of MCL-1 through mechanisms similar to those utilised by c-FOS, EGR1, NUR77, and others might aid in maintaining viability as these cells move along the differentiation pathway. Therefore, consequences of ELK-1 upregulation in irradiated cells might be strong differentiation as well as proliferation factor mobilising pool of surviving stem cells to compensate low number of enterocytes after irradiation.…”

“…The early response mechanism may also serve to restrict MCL-1 expression to specific windows of time (e.g., the initiation of a step forward in differentiation), preventing prolonged exposure of cells to the viability-promoting gene product and minimising the possibility of transformation 18 .…”