Distinct roles for extracellular-signal-regulated protein kinase (ERK) mitogen-activated protein kinases and phosphatidylinositol 3-kinase in the regulation of Mcl-1 synthesis

Alterations in the expression of various Bcl-2 family members may act as on e means by which a cell's survival may be regulated. The mechanism by which cytokines regulate expression of Bcl-2 family members was examined in the haemopoietic cell line TF-1. Cytokine-induced Mcl-1 protein expression was shown to be controlled through a pathway dependent upon phosphatidylinosito l 3-kinase (PI 3-kinase). The cytokine-induced increase in mRNA transcripti on was not dependent upon PI 3-kinase, thus dissociating the immediate-earl y transcription factors responsible for Mcl-1 transcription from the PI 3-k inase signalling pathway. In contrast, Mcl-1 mRNA levels were dependent upo n MEK [mitogen-activated protein kinase (MAPK)/extracellular-signal-regulat ed protein kinase kinase] activation, suggesting a role for the Ras/MEK/MAP K pathway in Mcl-1 transcription. Activation of PI 3-kinase was shown to be necessary to stimulate Mcl-1 protein translation. This was not due to any effect on prolonging the half-life of the protein. Finally, the lipid secon d messenger ceramide was shown to cause a reduction in Mcl-1 protein transl ation, probably via its ability to inhibit protein kinase B activation, pro viding further clues regarding the death-inducing effect of this lipid.