Notch-1 associates with IKK|[alpha]| and regulates IKK activity in cervical cancer cells

摘要

Notch-1 inhibits apoptosis in some transformed cells through incompletely understood mechanisms. Notch-1 can increase nuclear factor-kappa B (NF-κB) activity through a variety of mechanisms. Overexpression of cleaved Notch-1 in T-cell acute lymphoblastic leukemia cells activates NF-κB via interaction with the I kappa B kinase (IKK) signalosome. Concomitant activation of the Notch and NF-κB pathways has been described in a large series of cervical cancer specimens. Here, we show that wild-type, spontaneously expressed Notch-1 stimulates NF-κB activity in CaSki cervical cancer cells by associating with the IKK signalosome through IKKα. A significant fraction of tumor necrosis factor (TNF)-α-stimulated IκB kinase activity in CaSki cells is Notch-1-dependent. In addition, Notch-1 is found in the nucleus in association with IKKα at IKKα-stimulated promoters and is required for association of IKKα with these promoters under basal and TNF-α-stimulated conditions. Notch-1–IKKα complexes are found in normal human keratinocytes as well, suggesting that IKK regulation is a physiological function of Notch-1. Both Notch-1 and IKKα knockdown sensitize CaSki cells to cisplatin-induced apoptosis to equivalent extents. Our data indicate that Notch-1 regulates NF-κB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways.