The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways.

ABSTRACT: Mechanisms underlying apoptosis induced by concomitant interruption of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways were investigated in human leukemia cells. Inhibition of these pathways using the MEK inhibitor PD184352 or U0126 and the PI3K/Akt inhibitor perifosine strikingly induced apoptosis in multiple malignant human hematopoietic cells, and substantially reduced the colony-forming capacity of primary acute myeloblastic leukemia, but not normal CD34+ cells. These events were associated with pronounced Bim up-regulation, Mcl-1 down-regulation, marked Bak/Bax conformational change accompanied by Bax membrane translocation, and a pronounced increase in Bax/Bak association. Molecul

SUBMITTER: Rahmani M 

PROVIDER: S-EPMC2777129 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature