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  • Title: Notch-1 associates with IKKalpha and regulates IKK activity in cervical cancer cells.
    Author: Song LL, Peng Y, Yun J, Rizzo P, Chaturvedi V, Weijzen S, Kast WM, Stone PJ, Santos L, Loredo A, Lendahl U, Sonenshein G, Osborne B, Qin JZ, Pannuti A, Nickoloff BJ, Miele L.
    Journal: Oncogene; 2008 Oct 02; 27(44):5833-44. PubMed ID: 18560356.
    Abstract:
    Notch-1 inhibits apoptosis in some transformed cells through incompletely understood mechanisms. Notch-1 can increase nuclear factor-kappa B (NF-kappaB) activity through a variety of mechanisms. Overexpression of cleaved Notch-1 in T-cell acute lymphoblastic leukemia cells activates NF-kappaB via interaction with the I kappa B kinase (IKK) signalosome. Concomitant activation of the Notch and NF-kappaB pathways has been described in a large series of cervical cancer specimens. Here, we show that wild-type, spontaneously expressed Notch-1 stimulates NF-kappaB activity in CaSki cervical cancer cells by associating with the IKK signalosome through IKKalpha. A significant fraction of tumor necrosis factor (TNF)-alpha-stimulated IkappaB kinase activity in CaSki cells is Notch-1-dependent. In addition, Notch-1 is found in the nucleus in association with IKKalpha at IKKalpha-stimulated promoters and is required for association of IKKalpha with these promoters under basal and TNF-alpha-stimulated conditions. Notch-1-IKKalpha complexes are found in normal human keratinocytes as well, suggesting that IKK regulation is a physiological function of Notch-1. Both Notch-1 and IKKalpha knockdown sensitize CaSki cells to cisplatin-induced apoptosis to equivalent extents. Our data indicate that Notch-1 regulates NF-kappaB in cervical cancer cells at least in part via cytoplasmic and nuclear IKK-mediated pathways.
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