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- Title
Notch-1 associates with IKKα and regulates IKK activity in cervical cancer cells.
- Authors
Song, L L; Peng, Y; Yun, J; Rizzo, P; Chaturvedi, V; Weijzen, S; Kast, W M; Stone, P J B; Santos, L; Loredo, A; Lendahl, U; Sonenshein, G; Osborne, B; Qin, J-Z; Pannuti, A; Nickoloff, B J; Miele, L
- Abstract
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.Oncogene (2008) 27, 5833–5844; doi:10.1038/onc.2008.190; published online 16 June 2008
- Subjects
NOTCH genes; CELL transformation; CERVICAL cancer; LYMPHOBLASTIC leukemia; APOPTOSIS
- Publication
Oncogene, 2008, Vol 27, Issue 44, p5833
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2008.190