Inhibition of IκB kinase in Notch signaling activates FOXO3a

The notch signaling pathway is highly conserved and plays an important role in the regulation of cellular proliferation, differentiation and apoptosis. Constitutive activation of notch signaling results in excessive cellular proliferation and a wide range of malignan-cies. However, notch can also act as a tumor suppressor, and its inactivation has been associated with an increased risk of spontaneous squamous cell carcinoma. 1 signaling through the notch1 receptor is essential for normal T-cell fate specification as well as thymocyte maturation. 2 Approximately 50% of human T-ALLs display activating notch1 mutations, suggesting an important pathogenetic role for notch1 in TALL. 3 Activating mutations identified in the TALL cluster at the heterodi-merization domain (HD) and the proline, glu-tamine, serine and threonine (PesT) niCD1, respectively. nFκBs are sequestered in the cytoplasm by members of the iκB family (iκB-α, iκB-b and iκB-γ). when the iKK protein kinase complex signalosome phosphorylates iκB, nFκB translocates to the nucleus, dimerizes and engages in the transcription of downstream genes. nFκB-signaling cross-talks with notch at multiple levels. nFκB signaling results in increased expression of notch receptors and ligands, leading to augmented notch signal-ing, 4 and, conversely, activated notch signal-ing upregulates expression of nFκB members. 5 The nFκB pathway is constitutively activated in human TALL cells that harbor notch1 mutations. Moreover, it has been documented that iKK/nFκB signaling is essential for the maintenance of TALL , as leukemic cells that are unable to activate the iKK kinase complex rapidly enter apoptosis. Hence, the nFκB pathway is a potential molecular target for the treatment of TALL. 6 Accordingly, in the study by Buontempo et al. in this issue of Cell Cycle, the authors report the anti-proliferative effects induced by BMs-345541 (a highly selective iKK inhibitor) in three notch1-mutated TALL cell lines and in TALL primary cells from pediatric patients. BMs-345541 induced apoptosis and accumulation of cells in the G 2 /M phase of the cell cycle via inhibition of iKK/nFκB signaling. interestingly, they also showed that TALL cells treated with BMs-345541 displayed nuclear translocation of FOXO3a and restoration of its functions, including control of p21Cip1 expression levels. The human FOXO transcription factor family upregulates genes involved in the control of the cell cycle (p27Kip1 and p21Cip1) or in the induction of apoptosis. FOXO3a overexpres-sion inhibits tumor growth in vitro and tumor size in vivo in breast cancer cells. Cytoplasmic location of FOXO3a correlates with poor survival in breast cancer patients. 7 The …