MEK kinase 1 mediates the antiapoptotic effect of the Bcr-Abl oncogene through NF-κB activation

Nuclear factor-κB and inhibitor of κB kinase pathways in oncogenic initiation and progression

“…In addition, Bcr-Abl-induced NF-kB activation seems to involve the activation of the kinase MEK kinase 1 (MEKK1) (Nawata et al, 2003) (see Figure 2). Consistent with a role for NF-kB in Bcr-Ablassociated malignancies, NF-kB was found to be chronically active in CML and in Bcr-Abl-positive acute lymphocytic leukemias (Kirchner et al, 2003;Munzert et al, 2004;Cilloni et al, 2006).…”

MEK kinase 1 is essential for Bcr–Abl-induced STAT3 and self-renewal activity in embryonic stem cells

“…In addition, we previously showed that cell transformation induced by Bcr-Abl leads to increased expression of MEKK1, which then serves as a downstream target of Bcr-Abl, mediating an antiapoptotic effect (Nawata et al, 2003). To investigate the role of MEKK1 in BcrAbl-induced transformation of stem cells, we used a stable line of p210 Bcr-Abl-transfected MEKK1À/À ES cells to examine the effects of disrupting MEKK1 expression on the Bcr-Abl-induced undifferentiated phenotype and constitutive STAT3 activation.…”

Activation of the NF-κB pathway by the leukemogenic TEL-Jak2 and TEL-Abl fusion proteins leads to the accumulation of antiapoptotic IAP proteins and involves IKKα

“…Several mechanisms have been evoked for Bcr-Ablmediated NF-kB activation in hematopoietic cells including Ras-dependent and IKK-independent stimulation of nuclear translocation and transactivation function of p65/RelA (Reuther et al, 1998;Hanson et al, 2003;Kirchner et al, 2003) and implication of the MEK kinase 1 (MEKK1) (Nawata et al, 2003). Involvement of members of the src kinase family required for in vivo Bcr-Abl leukemogenic properties (Hu et al, 2004), and known to stimulate NIK activity and to phosphorylate IKK directly (Huang et al, 2003) has also been reported.…”