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Blood, 12 November 2009, Vol. 114, No. 20, pp. 4507-4516. Prepublished online as a Blood First Edition Paper on September 22, 2009; DOI 10.1182/blood-2008-09-177881. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2008-09-177881v1 114/20/4507    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Rahmani, M. Articles by Grant, S. PubMed PubMed Citation Articles by Rahmani, M. Articles by Grant, S. Related Collections Myeloid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA 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 Mohamed Rahmani1, Anh Anderson1, Joseph Reza Habibi1, Timothy Ryan Crabtree1, Mandy Mayo1, Hisashi Harada1, Andrea Ferreira-Gonzalez2, Paul Dent3, and Steven Grant1,3,4 Departments of 1 Medicine, 2 Pathology, 3 Biochemistry, and 4 Pharmacology, Virginia Commonwealth University and Massey Cancer Center, Richmond 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. Molecular studies using tet-inducible Akt, constitutively active MEK1, dominant-negative Akt, and MEK1 small interfering RNA revealed that inhibition of both MEK/ERK1/2 and Akt pathways plays a critical functional role in perifosine/PD184352-mediated lethality. Ectopic Mcl-1 expression potently inhibited perifosine/PD184352-induced apoptosis, as did Bak or Bax knockdown. Notably, knockdown of Bim, but not Bad, blocked Bak and Bax conformational change, inhibited Bax membrane translocation, diminished Bax/Bak binding, and sharply attenuated perifosine/PD184352-induced apoptosis. Finally, enforced expression of Bim significantly enhanced apoptosis induced by PI3K/Akt inhibitors, analogous to the effects of MEK1/2 inhibitors. Collectively, these findings suggest that Bim, and Mcl-1, but not Bad, integrate death signaling triggered by concomitant disruption of the PI3K/Akt and MEK1/2/ERK1/2 pathways in human leukemia cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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